Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RPA (replication protein A), the eukaryotic ssDNA (single-stranded DNA)-binding protein, participates in most cellular processes in response to genotoxic insults, such as NER (nucleotide excision repair), DNA, DSB (double-strand break) repair and activation of cell cycle checkpoint signalling. RPA interacts with XPA (xeroderma pigmentosum A) and functions in early stage of NER. We have shown that in cells the RPA-XPA complex disassociated upon exposure of cells to high dose of UV irradiation. The dissociation required replication stress and was partially attributed to tRPA hyperphosphorylation. Treatment of cells with CPT (camptothecin) and HU (hydroxyurea), which cause DSB DNA damage and replication fork collapse respectively and also leads to the disruption of RPA-XPA complex. Purified RPA and XPA were unable to form complex in vitro in the presence of ssDNA. We propose that the competition-based RPA switch among different DNA metabolic pathways regulates the dissociation of RPA with XPA in cells after DNA damage. The biological significances of RPA-XPA complex disruption in relation with checkpoint activation, DSB repair and RPA hyperphosphorylation are discussed.
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PMID:Replication-mediated disassociation of replication protein A-XPA complex upon DNA damage: implications for RPA handing off. 2257 86

SLX4, a coordinator of multiple DNA structure-specific endonucleases, is important for several DNA repair pathways. Noncovalent interactions of SLX4 with ubiquitin are required for localizing SLX4 to DNA interstrand crosslinks (ICLs), yet how SLX4 is targeted to other functional contexts remains unclear. Here, we show that SLX4 binds SUMO-2/3 chains via SUMO-interacting motifs (SIMs). The SIMs of SLX4 are dispensable for ICL repair but important for processing CPT-induced replication intermediates, suppressing fragile site instability, and localizing SLX4 to ALT telomeres. The localization of SLX4 to laser-induced DNA damage also requires the SIMs, as well as DNA end resection, UBC9, and MDC1. Furthermore, the SUMO binding of SLX4 enhances its interaction with specific DNA-damage sensors or telomere-binding proteins, including RPA, MRE11-RAD50-NBS1, and TRF2. Thus, the interactions of SLX4 with SUMO and ubiquitin increase its affinity for factors recognizing different DNA lesions or telomeres, helping to direct the SLX4 complex in distinct functional contexts.
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PMID:Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance. 2557 47

The RecQ helicases play roles in maintenance of genomic stability in species ranging from Escherichia coli to humans and interact with proteins involved in DNA metabolic pathways such as DNA repair, recombination, and replication. Our previous studies found that the Caenorhabditis elegans WRN-1 RecQ protein (a human WRN ortholog) exhibits ATP-dependent 3'-5' helicase activity and that the WRN-1 helicase is stimulated by RPA-1 on a long forked DNA duplex. However, the role of WRN-1 in response to S-phase associated with DSBs is unclear. We found that WRN-1 is involved in the checkpoint response to DSBs after CPT, inducing cell cycle arrest, is recruited to DSBs by RPA-1 and functions upstream of ATL-1 and ATM-1 for CHK-1 phosphorylation in the S-phase checkpoint. In addition, WRN-1 and RPA-1 recruitments to the DSBs require MRE-11, suggesting that DSB processing controlled by MRE-11 is important for WRN-1 at DSBs. The repair of CPT-induced DSBs is greatly reduced in the absence of WRN-1. These observations suggest that WRN-1 functions downstream of RPA-1 and upstream of CHK-1 in the DSB checkpoint pathway and is also required for the repair of DSB.
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PMID:The Caenorhabditis elegans Werner syndrome protein participates in DNA damage checkpoint and DNA repair in response to CPT-induced double-strand breaks. 2669 82

Several decades of research have identified Mcm10 hanging around the replisome making several critical contacts with a number of proteins but with no real disclosed function. Recently, the O'Donnell laboratory has been better able to map the interactions of Mcm10 with a larger Cdc45/GINS/MCM (CMG) unwinding complex placing it at the front of the replication fork. They have shown biochemically that Mcm10 has the impressive ability to strip off single-strand binding protein (RPA) and reanneal complementary DNA strands. This has major implications in controlling DNA unwinding speed as well as responding to various situations where fork reversal is needed. This work opens up a number of additional facets discussed here revolving around accessing the DNA junction for different molecular purposes within a crowded replisome. Abbreviations: alt-NHEJ: Alternative Nonhomologous End-Joining; CC: Coli-Coil motif; CMG: Cdc45/GINS/MCM2-7; CMGM: Cdc45/GINS/Mcm2-7/Mcm10; CPT: Camptothecin; CSB: Cockayne Syndrome Group B protein; CTD: C-Terminal Domain; DSB: Double-Strand Break; DSBR: Double-Strand Break Repair; dsDNA: Double-Stranded DNA; GINS: go-ichi-ni-san, Sld5-Psf1-Psf2-Psf3; HJ Dis: Holliday Junction dissolution; HJ Res: Holliday Junction resolution; HR: Homologous Recombination; ICL: Interstrand Cross-Link; ID: Internal Domain; MCM: Minichromosomal Maintenance; ND: Not Determined; NTD: N-Terminal Domain; PCNA: Proliferating Cell Nuclear Antigen; RPA: Replication Protein A; SA: Strand Annealing; SE: Strand Exchange; SEW: Steric Exclusion and Wrapping; ssDNA: Single-Stranded DNA; TCR: Transcription-Coupled Repair; TOP1: Topoisomerase.
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PMID:Fine-tuning of the replisome: Mcm10 regulates fork progression and regression. 3101 74