Abstract
Prevention and repair of DNA damage is essential for maintenance of genomic stability and cell survival. DNA replication during S-phase can be a source of DNA damage if endogenous or exogenous stresses impair the progression of replication forks. It has become increasingly clear that DNA-damage-response pathways do not only respond to the presence of damaged DNA, but also modulate DNA replication dynamics to prevent DNA damage formation during S-phase. Such observations may help explain the developmental defects or cancer predisposition caused by mutations in DNA-damage-response genes. The present review focuses on molecular mechanisms by which DNA-damage-response pathways control and promote replication dynamics in vertebrate cells. In particular, DNA damage pathways contribute to proper replication by regulating replication initiation, stabilizing transiently stalled forks, promoting replication restart and facilitating fork movement on difficult-to-replicate templates. If replication fork progression fails to be rescued, this may lead to DNA damage and genomic instability via nuclease processing of aberrant fork structures or incomplete sister chromatid separation during mitosis.
- cell cycle
- checkpoint
- DNA repair
- DNA helicase
- homologous recombination
- translesion synthesis
Abbreviations: AND-1, WD repeat and HMG-box DNA-binding protein 1; ASF1, anti-silencing function 1; ATM, ataxia telangiectasia mutated; ATR, ATM- and Rad3-related; BLM, Bloom syndrome, RecQ helicase-like; BRCA, breast cancer early onset; CAF-1, chromatin assembly factor 1; CDA, cytidine deaminase; CDC6, cell division cycle; CDK, cyclin-dependent kinase; CDT1, chromatin licensing and DNA replication factor 1; CHK, checkpoint kinase; D-loop, displacement loop; DDK, Dbf4/Drf1-dependent CDC7 kinase; DSB, double-strand break; EME1, essential meiotic endonuclease 1 homologue 1; EXO1, exonuclease 1; FA, Fanconi anaemia; FACT, facilitates chromatin transcription; FANCE, FA, complementation group E; GEN1, Gen endonuclease homologue 1; GINS, go-ichi-ni-san; HJ, Holliday junction; HLTF, helicase-like transcription factor; HR, homologous recombination; hRMI1, RecQ-mediated genome instability 1, homologue; MCM, mini-chromosome maintenance; MMS, methyl methanesulfonate; MRE11, meiotic recombination 11; MUS81, MUS81 endonuclease homologue; ORC, origin recognition complex; PARP, poly(ADP-ribose) polymerase; PCNA, proliferating cell nuclear antigen; PLK, Polo-like kinase; pre-RC, pre-replication complex; RFB, replication fork barrier; RFC, replication factor C; SHPRH, SNF2 histone linker PHD RING helicase; SMARCAL1, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1; ssDNA, single-stranded DNA; TIM, timeless homologue; TIPIN, TIMELESS-interacting protein; TLK, tousled-like kinase; TLS, translesion synthesis; TOP, topoisomerase; WRN, Werner syndrome, RecQ helicase-like; XRCC, X-ray repair complementing defective repair in Chinese hamster cells
- © The Authors Journal compilation © 2012 Biochemical Society
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April 2012
Volume: 443 Issue: 1
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