TP53 Regulates Transcription of DNA Repair Genes (Homo sapiens)

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4, 8, 11, 14, 18...304, 15, 18, 3941914, 2619111142114, 15, 18, 25, 33...114, 15, 25, 27, 394214, 26304nucleoplasmFANCI CCNK RAD51D gene TCEB3B TCEB3C POLR2I POLR2G NELFA SUPT16H CDK7 SSRP1 BRCA1 nascent mRNA p-S15,S20-TP53Tetramer:CCNK GeneTCEA1 DDB2POLR2J GTF2H2 FANCC GeneCDK7 TCEB2 p-S15,S20-TP53Tetramer:MLH1 GeneTCEB3CL BRCA1 gene MNAT1 MSH2 Gene POLR2K ATM Gene RAD51D gene FANCD2 Gene FANCC Gene POLR2I MNAT1 p-S15,S20-TP53Tetramer:FANCC GenePOLR2F ERCC3 GTF2F2 FANCI Gene p-S15,S20-TP53Tetramer:DDB2 GeneTCEB3CL TCEB2 MSH2 GeneTCEA1 CCNK:CDK12POLR2E SSRP1 GTF2H3 POLR2G p-T325,T331,S362,S374-FOS NELFCD GTF2F1 POLR2K ATR nascent mRNA POLR2F CDK13p-S15,S20-TP53 TCEA1 p-S15,S20-TP53 MDC1 nascent mRNA PMS2 GeneMLH1 Gene Mismatch RepairCDK9 ERCC3 POLR2J CHEK1 Gene POLR2B ATR Gene DNA Double-StrandBreak Repairp-SUPT5H GTF2H5 RAD51D ATM PMS2 Gene BRCA1 gene RAD51D nascent mRNA p-S15,S20-TP53 CDK9 SUPT4H1 CCNK RAD51D nascent mRNA GTF2F2 CTDP1 TCEB1 MDC1 Gene GTF2H5 POLR2L SUPT16H SSRP1 NELFCD CTDP1 GTF2H4 ATM nascent mRNA ATM nascent mRNA p-S63,S73-JUN BRCA1 nascent mRNA p-SUPT5H NELFA GTF2H2 POLR2H NELFB BRCA1 nascent mRNA ERCC2 NELFA SUPT4H1 ELL POLR2C MDC1 MDC1 nascent mRNA CTDP1 CCNK NELFE DNA repair genesregulated by CDK12p-S63,S73-JUN Nucleotide ExcisionRepairPOLR2B CCNK:CDK12:Elongation Complex at DNA Repair GenesRAD51D gene TCEB3CL2 CCNK Gene ATR nascent mRNA GTF2F2 TCEB3C CCNT1 CDK12 TCEB1 MDC1 Gene CDK7 MDC1 Gene POLR2B MDC1 nascent mRNA DDB2 Genep-S15,S20-TP53Tetramer:PMS2 Genep-T69,T71-ATF2 TCEB3 CCNK:CDK12:CDK12-Phosphorylated Elongation Complex at DNA repair genesBRCA1 GTF2H3 MSH2ERCC3 ADPPOLR2D CHEK1 nascent mRNA TCEB3 ATPPOLR2E TCEB3 CHEK1 Gene TCEB3B FANCD2 Gene CHEK1 Gene p-T325,T331,S362,S374-FOS GTF2F1 p-S15,S20-TP53 CCNT1 FANCI nascent mRNA TCEB1 POLR2D p-S15,S20-TP53 AP-1NELFE POLR2F FANCD2 Gene POLR2E FANCI nascent mRNA ATM Gene ATR Gene POLR2C ATR SUPT16H POLR2K ERCC2 ATR nascent mRNA GTF2H4 TCEB3B TCEB3C FANCD2 nascent mRNA p-S2,S5-POLR2A FANCI nascent mRNA CCNH BRCA1 gene POLR2I CCNT2 p-T69,T71-ATF2 POLR2L FANCI Gene CCNK DDB2 Gene TCEB2 NELFB POLR2J GTF2H1 ELL ATM Gene CDK9 FANCD2 Gene NELFB GTF2H3 FANCCp-S15,S20-TP53 GTF2H4 GTF2H2 PMS2POLR2L TCEB3CL2 MLH1 GeneFANCD2 nascent mRNA POLR2C POLR2H CDK12 NELFE CDK12CDK12 ATR Gene ERCC2 GTF2F1 TCEB3CL2 ATM nascent mRNA ATR Gene CCNK p-S15,S20-TP53 MLH1p-3S-POLR2A ATM Gene ELL CCNT2 CCNT1 CCNK GeneRAD51D gene GTF2H1 CCNK:CDK13POLR2D GTF2H1 CHEK1 nascent mRNA CCNT2 p-S2,S5-POLR2A CCNH FANCD2 nascent mRNA TCEB3CL MDC1 Gene p-S15,S20-TP53TetramerPOLR2G POLR2H NELFCD CHEK1 Gene AP-1:p-S15,S20-TP53Tetramer:MSH2 GeneFanconi AnemiaPathwayFANCD2 Elongation Complexat DNA Repair GenesCHEK1 nascent mRNA p-SUPT5H CDK13 BRCA1, ATR, FANCD2,FANCI, ATM, MDC1,CHEK1, RAD51DGTF2H5 FANCI Gene BRCA1 gene SUPT4H1 CHEK1 CCNH MNAT1 CCNKRAD51D nascent mRNA FANCI Gene 114116, 372, 5, 7, 10, 12...424199, 17, 21, 34, 38...29301, 3, 13, 16, 22...2629


Description

Several DNA repair genes contain p53 response elements and their transcription is positively regulated by TP53 (p53). TP53-mediated regulation probably ensures increased protein level of DNA repair genes under genotoxic stress.

TP53 directly stimulates transcription of several genes involved in DNA mismatch repair, including MSH2 (Scherer et al. 2000, Warnick et al. 2001), PMS2 and MLH1 (Chen and Sadowski 2005). TP53 also directly stimulates transcription of DDB2, involved in nucleotide excision repair (Tan and Chu 2002), and FANCC, involved in the Fanconi anemia pathway that repairs DNA interstrand crosslinks (Liebetrau et al. 1997). Other p53 targets that can influence DNA repair functions are RRM2B (Kuo et al. 2012), XPC (Fitch et al. 2003), GADD45A (Amundson et al. 2002), CDKN1A (Cazzalini et al. 2010) and PCNA (Xu and Morris 1999). Interestingly, the responsiveness of some of these DNA repair genes to p53 activation has been shown in human cells but not for orthologous mouse genes (Jegga et al. 2008, Tan and Chu 2002). Contrary to the positive modulation of nucleotide excision repair (NER) and mismatch repair (MMR), p53 can negatively modulate base excision repair (BER), by down-regulating the endonuclease APEX1 (APE1), acting in concert with SP1 (Poletto et al. 2016).<p>Expression of several DNA repair genes is under indirect TP53 control, through TP53-mediated stimulation of cyclin K (CCNK) expression (Mori et al. 2002). CCNK is the activating cyclin for CDK12 and CDK13 (Blazek et al. 2013). The complex of CCNK and CDK12 binds and phosphorylates the C-terminal domain of the RNA polymerase II subunit POLR2A, which is necessary for efficient transcription of long DNA repair genes, including BRCA1, ATR, FANCD2, FANCI, ATM, MDC1, CHEK1 and RAD51D. Genes whose transcription is regulated by the complex of CCNK and CDK12 are mainly involved in the repair of DNA double strand breaks and/or the Fanconi anemia pathway (Blazek et al. 2011, Cheng et al. 2012, Bosken et al. 2014, Bartkowiak and Greenleaf 2015, Ekumi et al. 2015). View original pathway at:Reactome.</div>

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Pathway is converted from Reactome ID: 6796648
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Reactome version: 66
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Reactome Author: Orlic-Milacic, Marija

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Bibliography

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History

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CompareRevisionActionTimeUserComment
101605view11:47, 1 November 2018ReactomeTeamreactome version 66
101142view21:33, 31 October 2018ReactomeTeamreactome version 65
100670view20:06, 31 October 2018ReactomeTeamreactome version 64
100220view16:51, 31 October 2018ReactomeTeamreactome version 63
99771view15:17, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99329view12:47, 31 October 2018ReactomeTeamreactome version 62
93822view13:38, 16 August 2017ReactomeTeamreactome version 61
93370view11:21, 9 August 2017ReactomeTeamreactome version 61
88391view15:15, 4 August 2016FehrhartOntology Term : 'regulatory pathway' added !
88390view15:14, 4 August 2016FehrhartOntology Term : 'DNA repair pathway' added !
86455view09:18, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AP-1:p-S15,S20-TP53 Tetramer:MSH2 GeneComplexR-HSA-6806565 (Reactome)
AP-1ComplexR-HSA-6806560 (Reactome)
ATM Gene ProteinENSG00000149311 (Ensembl)
ATM ProteinQ13315 (Uniprot-TrEMBL)
ATM nascent mRNA ProteinENST00000278616 (Ensembl)
ATPMetaboliteCHEBI:15422 (ChEBI)
ATR Gene ProteinENSG00000175054 (Ensembl)
ATR ProteinQ13535 (Uniprot-TrEMBL)
ATR nascent mRNA ProteinENST00000350721 (Ensembl)
BRCA1 ProteinP38398 (Uniprot-TrEMBL)
BRCA1 gene ProteinENSG00000012048 (Ensembl)
BRCA1 nascent mRNA ProteinENST00000357654 (Ensembl)
BRCA1, ATR, FANCD2,

FANCI, ATM, MDC1,

CHEK1, RAD51D
ComplexR-HSA-6797713 (Reactome)
CCNH ProteinP51946 (Uniprot-TrEMBL)
CCNK Gene ProteinENSG00000090061 (Ensembl)
CCNK GeneGeneProductENSG00000090061 (Ensembl)
CCNK ProteinO75909 (Uniprot-TrEMBL)
CCNK:CDK12:CDK12-Phosphorylated Elongation Complex at DNA repair genesComplexR-HSA-6797602 (Reactome)
CCNK:CDK12:Elongation Complex at DNA Repair GenesComplexR-HSA-6797614 (Reactome)
CCNK:CDK12ComplexR-HSA-6797095 (Reactome)
CCNK:CDK13ComplexR-HSA-6797094 (Reactome)
CCNKProteinO75909 (Uniprot-TrEMBL)
CCNT1 ProteinO60563 (Uniprot-TrEMBL)
CCNT2 ProteinO60583 (Uniprot-TrEMBL)
CDK12 ProteinQ9NYV4 (Uniprot-TrEMBL)
CDK12ProteinQ9NYV4 (Uniprot-TrEMBL)
CDK13 ProteinQ14004 (Uniprot-TrEMBL)
CDK13ProteinQ14004 (Uniprot-TrEMBL)
CDK7 ProteinP50613 (Uniprot-TrEMBL)
CDK9 ProteinP50750 (Uniprot-TrEMBL)
CHEK1 Gene ProteinENSG00000149554 (Ensembl)
CHEK1 ProteinO14757 (Uniprot-TrEMBL)
CHEK1 nascent mRNA ProteinENST00000438015 (Ensembl)
CTDP1 ProteinQ9Y5B0 (Uniprot-TrEMBL)
DDB2 Gene ProteinENSG00000134574 (Ensembl)
DDB2 GeneGeneProductENSG00000134574 (Ensembl)
DDB2ProteinQ92466 (Uniprot-TrEMBL)
DNA Double-Strand Break RepairPathwayR-HSA-5693532 (Reactome) Double-strand breaks (DSBs), one of the most deleterious types of DNA damage along with interstrand crosslinks, are caused by ionizing radiation or certain chemicals such as bleomycin. DSBs also occur physiologically, during the processes of DNA replication, meiotic exchange, and V(D)J recombination.

DSBs are sensed (detected) by the MRN complex. Binding of the MRN complex to the DSBs usually triggers ATM kinase activation, thus initiating the DNA double strand break response. ATM phosphorylates a number of proteins involved in DNA damage checkpoint signaling, as well as proteins directly involved in the repair of DNA DSBs. DSBs are repaired via homology directed repair (HDR) or via nonhomologous end-joining (NHEJ).

HDR requires resection of DNA DSB ends. Resection creates 3'-ssDNA overhangs which then anneal with a homologous DNA sequence. This homologous sequence can then be used as a template for DNA repair synthesis that bridges the DSB. HDR preferably occurs through the error-free homologous recombination repair (HRR), but can also occur through the error-prone single strand annealing (SSA), or the least accurate microhomology-mediated end joining (MMEJ). MMEJ takes place when DSB response cannot be initiated.

While HRR is limited to actively dividing cells with replicated DNA, error-prone NHEJ pathway functions at all stages of the cell cycle, playing the predominant role in both the G1 phase and in S-phase regions of DNA that have not yet replicated. During NHEJ, the Ku70:Ku80 heterodimer (also known as the Ku complex or XRCC5:XRCC6) binds DNA DSB ends, competing away the MRN complex and preventing MRN-mediated resection of DNA DSB ends. The catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs, PRKDC) is then recruited to DNA-bound Ku to form the DNA-PK holoenzyme. Two DNA-PK complexes, one at each side of the break, bring DNA DSB ends together, joining them in a synaptic complex. DNA-PK complex recruits DCLRE1C (ARTEMIS) to DNA DSB ends, leading to trimming of 3'- and 5'-overhangs at the break site, followed by ligation.

For review of this topic, please refer to Ciccia and Elledge 2010.

DNA repair genes regulated by CDK12ComplexR-HSA-6797615 (Reactome)
ELL ProteinP55199 (Uniprot-TrEMBL)
ERCC2 ProteinP18074 (Uniprot-TrEMBL)
ERCC3 ProteinP19447 (Uniprot-TrEMBL)
Elongation Complex at DNA Repair GenesComplexR-HSA-6797611 (Reactome)
FANCC Gene ProteinENSG00000158169 (Ensembl)
FANCC GeneGeneProductENSG00000158169 (Ensembl)
FANCCProteinQ00597 (Uniprot-TrEMBL)
FANCD2 Gene ProteinENSG00000144554 (Ensembl)
FANCD2 ProteinQ9BXW9 (Uniprot-TrEMBL)
FANCD2 nascent mRNA ProteinENST00000419585 (Ensembl)
FANCI Gene ProteinENSG00000140525 (Ensembl)
FANCI ProteinQ9NVI1 (Uniprot-TrEMBL)
FANCI nascent mRNA ProteinENST00000310775 (Ensembl)
Fanconi Anemia PathwayPathwayR-HSA-6783310 (Reactome) Fanconi anemia (FA) is a genetic disease of genome instability characterized by congenital skeletal defects, aplastic anemia, susceptibility to leukemias, and cellular sensitivity to DNA damaging agents. Patients with FA have been categorized into at least 15 complementation groups (FA-A, -B, -C, -D1, -D2, -E, -F, -G, -I, -J, -L, -M, -N, -O and -P). These complementation groups correspond to the genes FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCJ/BRIP1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C and FANCP/SLX4. Eight of these proteins, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM, together with FAAP24, FAAP100, FAAP20, APITD1 and STRA13, form a nuclear complex termed the FA core complex. The FA core complex is an E3 ubiquitin ligase that recognizes and is activated by DNA damage in the form of interstrand crosslinks (ICLs), triggering monoubiquitination of FANCD2 and FANCI, which initiates repair of ICL-DNA.

FANCD2 and FANCI form a complex and are mutually dependent on one another for their respective monoubiquitination. After DNA damage and during S phase, FANCD2 localizes to discrete nuclear foci that colocalize with proteins involved in homologous recombination repair, such as BRCA1 and RAD51. The FA pathway is regulated by ubiquitination and phosphorylation of FANCD2 and FANCI. ATR-dependent phosphorylation of FANCI and FANCD2 promotes monoubiquitination of FANCD2, stimulating the FA pathway (Cohn and D'Andrea 2008, Wang 2007). The complex of USP1 and WDR48 (UAF1) is responsible for deubiquitination of FANCD2 and negatively regulates the FA pathway (Cohn et al. 2007).

Monoubiquitinated FANCD2 recruits DNA nucleases, including SLX4 (FANCP) and FAN1, which unhook the ICL from one of the two covalently linked DNA strands. The DNA polymerase nu (POLN) performs translesion DNA synthesis using the DNA strand with unhooked ICL as a template, thereby bypassing the unhooked ICL. The unhooked ICL is subsequently removed from the DNA via nucleotide excision repair (NER). Incision of the stalled replication fork during the unhooking step generates a double strand break (DSB). The DSB is repaired via homologous recombination repair (HRR) and involves the FA genes BRCA2 (FANCD1), PALB2 (FANCN) and BRIP1 (FANCJ) (reviewed by Deans and West 2011, Kottemann and Smogorzewska 2013). Homozygous mutations in BRCA2, PALB2 or BRIP1 result in Fanconi anemia, while heterozygous mutations in these genes predispose carriers to primarily breast and ovarian cancer. Well established functions of BRCA2, PALB2 and BRIP1 in DNA repair are BRCA1 dependent, but it is not yet clear whether there are additional roles for these proteins in the Fanconi anemia pathway that do not rely on BRCA1 (Evans and Longo 2014, Jiang and Greenberg 2015). Heterozygous BRCA1 mutations predispose carriers to breast and ovarian cancer with high penetrance. Complete loss of BRCA1 function is embryonic lethal. It has only recently been reported that a partial germline loss of BRCA1 function via mutations that diminish protein binding ability of the BRCT domain of BRCA1 result in a FA-like syndrome. BRCA1 has therefore been designated as the FANCS gene (Jiang and Greenberg 2015).

The FA pathway is involved in repairing DNA ICLs that arise by exposure to endogenous mutagens produced as by-products of normal cellular metabolism, such as aldehyde containing compounds. Disruption of the aldehyde dehydrogenase gene ALDH2 in FANCD2 deficient mice leads to severe developmental defects, early lethality and predisposition to leukemia. In addition to this, the double knockout mice are exceptionally sensitive to ethanol consumption, as ethanol metabolism results in accumulated levels of aldehydes (Langevin et al. 2011).

GTF2F1 ProteinP35269 (Uniprot-TrEMBL)
GTF2F2 ProteinP13984 (Uniprot-TrEMBL)
GTF2H1 ProteinP32780 (Uniprot-TrEMBL)
GTF2H2 ProteinQ13888 (Uniprot-TrEMBL)
GTF2H3 ProteinQ13889 (Uniprot-TrEMBL)
GTF2H4 ProteinQ92759 (Uniprot-TrEMBL)
GTF2H5 ProteinQ6ZYL4 (Uniprot-TrEMBL)
MDC1 Gene ProteinENSG00000137337 (Ensembl)
MDC1 ProteinQ14676 (Uniprot-TrEMBL)
MDC1 nascent mRNA ProteinENST00000376406 (Ensembl)
MLH1 Gene ProteinENSG00000076242 (Ensembl)
MLH1 GeneGeneProductENSG00000076242 (Ensembl)
MLH1ProteinP40692 (Uniprot-TrEMBL)
MNAT1 ProteinP51948 (Uniprot-TrEMBL)
MSH2 Gene ProteinENSG00000095002 (Ensembl)
MSH2 GeneGeneProductENSG00000095002 (Ensembl)
MSH2ProteinP43246 (Uniprot-TrEMBL)
Mismatch RepairPathwayR-HSA-5358508 (Reactome) The mismatch repair (MMR) system corrects single base mismatches and small insertion and deletion loops (IDLs) of unpaired bases. MMR is primarily associated with DNA replication and is highly conserved across prokaryotes and eukaryotes. MMR consists of the following basic steps: a sensor (MutS homologue) detects a mismatch or IDL, the sensor activates a set of proteins (a MutL homologue and an exonuclease) that select the nascent DNA strand to be repaired, nick the strand, exonucleolytically remove a region of nucleotides containing the mismatch, and finally a DNA polymerase resynthesizes the strand and a ligase seals the remaining nick (reviewed in Kolodner and Marsischkny 1999, Iyer et al. 2006, Li 2008, Fukui 2010, Jiricny 2013).
Humans have 2 different MutS complexes. The MSH2:MSH6 heterodimer (MutSalpha) recognizes single base mismatches and small loops of one or two unpaired bases. The MSH2:MSH3 heterodimer (MutSbeta) recognizes loops of two or more unpaired bases. Upon binding a mismatch, the MutS complex becomes activated in an ATP-dependent manner allowing for subsequent downstream interactions and movement on the DNA substrate. (There are two mechanisms proposed: a sliding clamp and a switch diffusion model.) Though the order of steps and structural details are not fully known, the activated MutS complex interacts with MLH1:PMS2 (MutLalpha) and PCNA, the sliding clamp present at replication foci. The role of PCNA is multifaceted as it may act as a processivity factor in recruiting MMR proteins to replicating DNA, interact with MLH1:PMS2 and Exonuclease 1 (EXO1) to initiate excision of the recently replicated strand and direct DNA polymerase delta to initiate replacement of bases. MLH1:PMS2 makes an incision in the strand to be repaired and EXO1 extends the incision to make a single-stranded gap of up to 1 kb that removes the mismatched base(s). (Based on assays of purified human proteins, there is also a variant of the mismatch repair pathway that does not require EXO1, however the mechanism is not clear. EXO1 is almost always required, it is possible that the exonuclease activity of DNA polymerase delta may compensate in some situations and it has been proposed that other endonucleases may perform redundant functions in the absence of EXO1.) RPA binds the single-stranded region and a new strand is synthesized across the gap by DNA polymerase delta. The remaining nick is sealed by DNA ligase I (LIG1).
Concentrations of MMR proteins MSH2:MSH6 and MLH1:PMS2 increase in human cells during S phase and are at their highest level and activity during this phase of the cell cycle (Edelbrock et al. 2009). Defects in MSH2, MSH6, MLH1, and PMS2 cause hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) (reviewed in Martin-Lopez and Fishel 2013).
NELFA ProteinQ9H3P2 (Uniprot-TrEMBL)
NELFB ProteinQ8WX92 (Uniprot-TrEMBL)
NELFCD ProteinQ8IXH7 (Uniprot-TrEMBL)
NELFE ProteinP18615 (Uniprot-TrEMBL)
Nucleotide Excision RepairPathwayR-HSA-5696398 (Reactome) Nucleotide excision repair (NER) was first described in the model organism E. coli in the early 1960s as a process whereby bulky base damage is enzymatically removed from DNA, facilitating the recovery of DNA synthesis and cell survival. Deficient NER processes have been identified from the cells of cancer-prone patients with different variants of xeroderma pigmentosum (XP), trichothiodystrophy (TTD), and Cockayne's syndrome. The XP cells exhibit an ultraviolet radiation hypersensitivity that leads to a hypermutability response to UV, offering a direct connection between deficient NER, increased mutation rate, and cancer. While the NER pathway in prokaryotes is unique, the pathway utilized in yeast and higher eukaryotes is highly conserved.
NER is involved in the repair of bulky adducts in DNA, such as UV-induced photo lesions (both 6-4 photoproducts (6-4 PPDs) and cyclobutane pyrimidine dimers (CPDs)), as well as chemical adducts formed from exposure to aflatoxin, benzopyrene and other genotoxic agents. Specific proteins have been identified that participate in base damage recognition, cleavage of the damaged strand on both sides of the lesion, and excision of the oligonucleotide bearing the lesion. Reparative DNA synthesis and ligation restore the strand to its original state.
NER consists of two related pathways called global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER). The pathways differ in the way in which DNA damage is initially recognized, but the majority of the participating molecules are shared between these two branches of NER. GG-NER is transcription-independent, removing lesions from non-coding DNA strands, as well as coding DNA strands that are not being actively transcribed. TC-NER repairs damage in transcribed strands of active genes.
Several of the proteins involved in NER are key components of the basal transcription complex TFIIH. An ubiquitin ligase complex composed of DDB1, CUL4A or CUL4B and RBX1 participates in both GG-NER and TC-NER, implying an important role of ubiquitination in NER regulation. The establishment of mutant mouse models for NER genes and other DNA repair-related genes has been useful in demonstrating the associations between NER defects and cancer.
For past and recent reviews of nucleotide excision repair, please refer to Lindahl and Wood 1998, Friedberg et al. 2002, Christmann et al. 2003, Hanawalt and Spivak 2008, Marteijn et al. 2014).
PMS2 Gene ProteinENSG00000122512 (Ensembl)
PMS2 GeneGeneProductENSG00000122512 (Ensembl)
PMS2ProteinP54278 (Uniprot-TrEMBL)
POLR2B ProteinP30876 (Uniprot-TrEMBL)
POLR2C ProteinP19387 (Uniprot-TrEMBL)
POLR2D ProteinO15514 (Uniprot-TrEMBL)
POLR2E ProteinP19388 (Uniprot-TrEMBL)
POLR2F ProteinP61218 (Uniprot-TrEMBL)
POLR2G ProteinP62487 (Uniprot-TrEMBL)
POLR2H ProteinP52434 (Uniprot-TrEMBL)
POLR2I ProteinP36954 (Uniprot-TrEMBL)
POLR2J ProteinP52435 (Uniprot-TrEMBL)
POLR2K ProteinP53803 (Uniprot-TrEMBL)
POLR2L ProteinP62875 (Uniprot-TrEMBL)
RAD51D ProteinO75771 (Uniprot-TrEMBL)
RAD51D gene ProteinENSG00000185379 (Ensembl)
RAD51D nascent mRNA ProteinENST00000345365 (Ensembl)
SSRP1 ProteinQ08945 (Uniprot-TrEMBL)
SUPT16H ProteinQ9Y5B9 (Uniprot-TrEMBL) DSIF is a heterodimer consisting of hSPT4 (human homolog of yeast Spt4- p14) and hSPT5 (human homolog of yeast Spt5-p160). DSIF association with Pol II may be enabled by Spt5 binding to Pol II creating a scaffold for NELF binding (Wada et al.,1998). Spt5 subunit of DSIF can be phosphorylated by P-TEFb.
SUPT4H1 ProteinP63272 (Uniprot-TrEMBL)
TCEA1 ProteinP23193 (Uniprot-TrEMBL)
TCEB1 ProteinQ15369 (Uniprot-TrEMBL)
TCEB2 ProteinQ15370 (Uniprot-TrEMBL)
TCEB3 ProteinQ14241 (Uniprot-TrEMBL)
TCEB3B ProteinQ8IYF1 (Uniprot-TrEMBL)
TCEB3C ProteinQ8NG57 (Uniprot-TrEMBL)
TCEB3CL ProteinQ3SY89 (Uniprot-TrEMBL)
TCEB3CL2 ProteinA6NLF2 (Uniprot-TrEMBL)
p-3S-POLR2A ProteinP24928 (Uniprot-TrEMBL)
p-S15,S20-TP53 Tetramer:CCNK GeneComplexR-HSA-6796650 (Reactome)
p-S15,S20-TP53 Tetramer:DDB2 GeneComplexR-HSA-6806601 (Reactome)
p-S15,S20-TP53 Tetramer:FANCC GeneComplexR-HSA-6806590 (Reactome)
p-S15,S20-TP53 Tetramer:MLH1 GeneComplexR-HSA-6806584 (Reactome)
p-S15,S20-TP53 Tetramer:PMS2 GeneComplexR-HSA-6806574 (Reactome)
p-S15,S20-TP53 TetramerComplexR-HSA-3222171 (Reactome)
p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S2,S5-POLR2A ProteinP24928 (Uniprot-TrEMBL) The C-terminal domain (CTD) of POLR2A contains about 52 repeats of the consensus heptad YSPTSPS. Serines-2 and 5 of the heptads are phosphorylated in RNA polymerase II initiating transcription of protein coding genes. The exact repeats that are phosphorylated are not known.
p-S63,S73-JUN ProteinP05412 (Uniprot-TrEMBL)
p-SUPT5H ProteinO00267 (Uniprot-TrEMBL)
p-T325,T331,S362,S374-FOS ProteinP01100 (Uniprot-TrEMBL)
p-T69,T71-ATF2 ProteinP15336 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-6797606 (Reactome)
AP-1:p-S15,S20-TP53 Tetramer:MSH2 GeneArrowR-HSA-6806394 (Reactome)
AP-1:p-S15,S20-TP53 Tetramer:MSH2 GeneArrowR-HSA-6806412 (Reactome)
AP-1R-HSA-6806412 (Reactome)
ATPR-HSA-6797606 (Reactome)
BRCA1, ATR, FANCD2,

FANCI, ATM, MDC1,

CHEK1, RAD51D
ArrowR-HSA-6797712 (Reactome)
CCNK GeneR-HSA-6796647 (Reactome)
CCNK GeneR-HSA-6796649 (Reactome)
CCNK:CDK12:CDK12-Phosphorylated Elongation Complex at DNA repair genesArrowR-HSA-6797606 (Reactome)
CCNK:CDK12:CDK12-Phosphorylated Elongation Complex at DNA repair genesArrowR-HSA-6797712 (Reactome)
CCNK:CDK12:Elongation Complex at DNA Repair GenesArrowR-HSA-6797616 (Reactome)
CCNK:CDK12:Elongation Complex at DNA Repair GenesR-HSA-6797606 (Reactome)
CCNK:CDK12:Elongation Complex at DNA Repair Genesmim-catalysisR-HSA-6797606 (Reactome)
CCNK:CDK12ArrowR-HSA-6797090 (Reactome)
CCNK:CDK12R-HSA-6797616 (Reactome)
CCNK:CDK13ArrowR-HSA-6797100 (Reactome)
CCNKArrowR-HSA-6796647 (Reactome)
CCNKR-HSA-6797090 (Reactome)
CCNKR-HSA-6797100 (Reactome)
CDK12R-HSA-6797090 (Reactome)
CDK13R-HSA-6797100 (Reactome)
DDB2 GeneR-HSA-6806417 (Reactome)
DDB2 GeneR-HSA-6806423 (Reactome)
DDB2ArrowR-HSA-6806423 (Reactome)
DNA repair genes regulated by CDK12R-HSA-6797712 (Reactome)
Elongation Complex at DNA Repair GenesR-HSA-6797616 (Reactome)
FANCC GeneR-HSA-6806419 (Reactome)
FANCC GeneR-HSA-6806425 (Reactome)
FANCCArrowR-HSA-6806425 (Reactome)
MLH1 GeneR-HSA-6806392 (Reactome)
MLH1 GeneR-HSA-6806413 (Reactome)
MLH1ArrowR-HSA-6806392 (Reactome)
MSH2 GeneR-HSA-6806394 (Reactome)
MSH2 GeneR-HSA-6806412 (Reactome)
MSH2ArrowR-HSA-6806394 (Reactome)
PMS2 GeneR-HSA-6806405 (Reactome)
PMS2 GeneR-HSA-6806408 (Reactome)
PMS2ArrowR-HSA-6806405 (Reactome)
R-HSA-6796647 (Reactome) TP53 (p53) binding to the p53 response element in the first intron of the CCNK (cyclin K) gene stimulates CCNK transcription (Mori et al. 2002).
R-HSA-6796649 (Reactome) TP53 (p53) binds p53 response element located in the first intron of the CCNK (cyclin K) gene (Mori et al. 2002).
R-HSA-6797090 (Reactome) Cyclin K (CCNK) forms a complex with CDK12 (Blazek et al. 2011).
R-HSA-6797100 (Reactome) Cyclin K (CCNK) forms a complex with CDK13 (Blazek et al. 2011).
R-HSA-6797606 (Reactome) CDK12, in complex with CCNK (cyclin K), phosphorylates heptapeptide repeats in the C-terminal domain (CTD) of the RNA polymerase II (RNA Pol II) subunit POLR2A. CDK12 may require phosphorylation of its threonine residue T893 to achieve full catalytic activity, but the activating kinase is not known. CDK12-mediated phosphorylation of the CTD of POLR2A occurs after the heptapeptide repeats in the CTD of POLR2A undergo phosphorylation by the CDK9-containing P-TEFb complex. It is unclear whether CDK12 acts on the second serine or the fifth serine or both in the YSPTSPS repeats. The mammalian POLR2A contains 52 heptapeptide repeats that start at amino acid position 1615. The exact localization of CDK9 and CDK12 target sites relative to the full-length POLR2A is not known. CDK12-mediated phosphorylation of the pre-phosphorylated RNA Pol II complex is important for the transcription of a group of genes with long and complex structures, involved in DNA repair (Blazek et al. 2011, Cheng et al. 2012, Bosken et al. 2014, Bartkowiak and Greenleaf 2015, Liang et al. 2015).
R-HSA-6797616 (Reactome) The complex of CDK12 and CCNK (cyclin K) associates with the RNA polymerase II (RNA Pol II) elongation complex at DNA repair genes encoding long primary transcripts, such as BRCA1, ATR, FANCI, FANCD2, ATM, MDC1, CHEK1, RAD51D and APEX1 (Blazek et al. 2011, Bartkowiak and Greenleaf 2015, Ekumi et al. 2015, Liang et al. 2015).
R-HSA-6797712 (Reactome) CDK12-mediated phosphorylation of the C-terminal domain (CTD) of the RNA polymerase II (RNA Pol II) subunit POLR2A (Rpb1) positively regulates transcription and, hence, expression of a set of DNA repair genes that encode long primary transcripts. CDK12, in complex with the TP53-regulated CCNK (cyclin K), phosphorylates POLR2A that was pre-phosphorylated by the CDK9-containing complex P-TEFb. CDK12-mediated phosphorylation of POLR2A is thought to increase the processivity of the RNA Pol II, enabling efficient transcription of long DNA repair genes (Blazek et al. 2011, Cheng et al. 2012, Bosken et al. 2014, Bartkowiak and Greenleaf 2015). CDK12 was shown to colocalize with the RNA Pol II complex at FANCD2, FANCI, ATM, CHEK1, MDC1, RAD51D and ATR gene loci (Ekumi et al. 2015) and to be necessary for achieving sufficient BRCA1 expression (Blazek et al. 2011). CDK12 positively regulates the expression of APEX1, involved in base excision repair (Liang et al. 2015). Recurrent CDK12 mutations are found in ovarian cancer. These mutations affect either the catalytic cleft of CDK12 or disable the interaction of CDK12 with CCNK, resulting in the loss of CDK12 function. Ovarian tumors that harbour inactivating CDK12 mutations exhibit decreased BRCA1 levels, defective homologous recombination repair, increased sensitivity to DNA crosslinking agents, and sensitivity to PARP inhibitors (Joshi et al. 2014, Ekumi et al. 2015).
R-HSA-6806392 (Reactome) TP53 (p53) stimulates transcription of the MLH1 gene, involved in DNA mismatch repair, by binding to the p53 response element in the first intron of the MLH1 gene (Chen and Sadowski 2005).
R-HSA-6806394 (Reactome) TP53 and the AP-1 transcription factor complex cooperatively stimulate transcription of the MSH2 gene, involved in DNA mismatch repair, by binding to adjacent sites in the MSH2 promoter (Scherer et al. 2001). TP53 may stimulate transcription of MSH2 independently of the AP-1 complex when bound to a different p53 response element in the MSH2 promoter (Warnick et al. 2001).
R-HSA-6806405 (Reactome) TP53 (p53) stimulates transcription of PMS2, involved in DNA mismatch repair, by binding to the p53 response element in the first intron of the PMS2 gene (Chen and Sadowski 2005).
R-HSA-6806408 (Reactome) TP53 (p53) binds the p53 response element in the first intron of the PMS2 gene (Chen and Sadowski 2005).
R-HSA-6806412 (Reactome) TP53 (p53) binds to the p53 response element in the promoter of the MSH2 gene. The p53 response element is flanked by two AP-1 sites. The AP-1 transcription factor complex binds the MSH2 promoter cooperatively with TP53 (Scherer et al. 2000). An additional p53 response element in closer proximity to the MSH2 transcription start site has been reported that does not involve a nearby AP-1 binding site (Warnick et al. 2001).
R-HSA-6806413 (Reactome) TP53 (p53) binds the p53 response element in the first intron of the MLH1 gene (Chen and Sadowski 2005).
R-HSA-6806417 (Reactome) TP53 (p53) binds the p53 response element in the 5'UTR-encoding region of the DDB2 gene. The p53 response element is present in the human DDB2 gene, but absent from the mouse Ddb2 gene (Tan and Chu 2002).
R-HSA-6806419 (Reactome) TP53 (p53) binds the p53 response element in the promoter of the FANCC (Fanconi anemia group C) gene (Liebetrau et al. 1997).
R-HSA-6806423 (Reactome) TP53 (p53) stimulates transcription of the DDB2 gene, involved in nucleotide excision repair, by binding to the p53 response element in the 5'UTR-encoding region of the DDB2 gene (Tan and Chu 2002).
R-HSA-6806425 (Reactome) TP53 (p53) stimulates transcription of the FANCC (Fanconi anemia group C) gene, involved in the Fanconi anemia pathway that repairs DNA interstrand crosslinks, by binding to the p53 response element in the FANCC promoter (Liebetrau et al. 1997).
p-S15,S20-TP53 Tetramer:CCNK GeneArrowR-HSA-6796647 (Reactome)
p-S15,S20-TP53 Tetramer:CCNK GeneArrowR-HSA-6796649 (Reactome)
p-S15,S20-TP53 Tetramer:DDB2 GeneArrowR-HSA-6806417 (Reactome)
p-S15,S20-TP53 Tetramer:DDB2 GeneArrowR-HSA-6806423 (Reactome)
p-S15,S20-TP53 Tetramer:FANCC GeneArrowR-HSA-6806419 (Reactome)
p-S15,S20-TP53 Tetramer:FANCC GeneArrowR-HSA-6806425 (Reactome)
p-S15,S20-TP53 Tetramer:MLH1 GeneArrowR-HSA-6806392 (Reactome)
p-S15,S20-TP53 Tetramer:MLH1 GeneArrowR-HSA-6806413 (Reactome)
p-S15,S20-TP53 Tetramer:PMS2 GeneArrowR-HSA-6806405 (Reactome)
p-S15,S20-TP53 Tetramer:PMS2 GeneArrowR-HSA-6806408 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6796649 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6806408 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6806412 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6806413 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6806417 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6806419 (Reactome)

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