Mechanisms of Dealing with DNA Damage-Induced Replication Problems

Abstract

During every S phase, cells need to duplicate their genomes so that both daughter cells inherit complete copies of genetic information. Given the large size of mammalian genomes and the required precision of DNA replication, genome duplication requires highly fine-tuned corrective and quality control processes. A major threat to the accuracy and efficiency of DNA synthesis is the presence of DNA lesions, caused by both endogenous and exogenous damaging agents. Replicative DNA polymerases, which carry out the bulk of DNA synthesis, evolved to do their job extremely precisely and efficiently. However, they are unable to use damaged DNA as a template and, consequently, are stopped at most DNA lesions. Failure to restart such stalled replication forks can result in major chromosomal aberrations and lead to cell dysfunction or death. Therefore, a well-coordinated response to replication perturbation is essential for cell survival and fitness. Here we review how this response involves activating checkpoint signaling and the use of specialized pathways promoting replication restart. Checkpoint signaling adjusts cell cycle progression to the emergency situation and thus gives cells more time to deal with the damage. Replication restart is mediated by two pathways. Homologous recombination uses homologous DNA sequence to repair or bypass the lesion and is therefore mainly error free. Error-prone translesion synthesis employs specialized, low fidelity polymerases to bypass the damage.

Distinct Roles of FANCO/RAD51C Protein in DNA Damage Signaling and Repair

“…Thus, it remains unclear how RAD51C differentially regulate short tract gene conversions and LTGC. HR plays a major role in the repair of DNA lesions associated with replication and in the recovery of stalled/collapsed replication forks (7,9,17,46). RAD51C-deficient cells were hypersensitive to genotoxic agents that induce genome-wide DSBs and DSGs, indicating the critical role of RAD51C in HR function.…”

“…Strikingly, RAD51C-deficient cells also displayed chromatidtype errors, providing evidence that RAD51C is a novel component in the FA and BRCA pathway of DNA repair. BRCA pathway also plays a critical role in the repair of genome-wide DSBs and DSGs that arise during replication (7,9,26). The BRCA proteins BRCA1, BRCA2, and PALB2 have been shown to regulate intra-S-phase checkpoint (62)(63)(64)(65).…”

“…Because the copied information is accurate, SCR is potentially an error-free pathway. HR also plays a critical role in the repair of daughter strand gaps (DSGs) that arise as a result of replication fork stalling and facilitates replication fork recovery (4,(7)(8)(9). Furthermore, in collaboration with nucleotide excision repair and translesion synthesis, HR is involved in the repair of DNA interstrand cross-links (ICLs) (10,11).…”

The Role of the Human Psoralen 4 (hPso4) Protein Complex in Replication Stress and Homologous Recombination

“…There is now compelling evidence that HR plays an essential role in the repair of DSBs that arise during DNA replication, even in the absence of exogenous DNA damage (13,33). The increased sensitivity of hPos4-depleted cells to a PARP inhibitor that causes DSBs in a replication-dependent manner and the defect in the repair of site-specific DSBs by HR in these cells provide strong evidence that the hPso4 complex participates in the repair of replicationassociated DSBs via a homology-dependent pathway.…”

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

“…A recent study using inhibitors of ATR and CHK1 reported that the abundance of ssDNA during replication stress exhausts the available pool of RPA increasing the likelihood that unprotected ssDNA will be cleaved by endonucleases (13). Stalled forks are believed to be repaired primarily, but not exclusively, by homologous recombination (14,15). The resulting DNA structure intermediates generated during homologous recombination repair (HRR; i.e., Holliday junctions) are cleaved by endonucleases such as MUS81/EME1 yielding a doublestranded break.…”