The DNA damage checkpoint response to replication stress: A Game of Forks

Abstract

Conditions challenging replication fork progression, collectively referred to as replication stress, represent a major source of genomic instability and are associated to cancer onset. The replication checkpoint, a specialized branch of the DNA damage checkpoint, monitors fork problems, and triggers a cellular response aimed at preserving genome integrity. Here, we review the mechanisms by which the replication checkpoint monitors and responds to replication stress, focusing on the checkpoint-mediated pathways contributing to protect replication fork integrity. We discuss how cells achieve checkpoint signaling inactivation once replication stress is overcome and how a failure to timely revert checkpoint-mediated changes in cellular physiology might impact on replication dynamics and genome integrity. We also highlight the checkpoint function as an anti-cancer barrier preventing cells malignant transformation following oncogene-induced replication stress.

Human CST abundance determines recovery from diverse forms of DNA damage and replication stress

“…4,59 Interestingly while MMC elicits the checkpoint, ATR activation is via the Fanconi anemia core complex rather than the canonical pathway involving Rad17. [59][60][61] Thus, our findings raise the possibility that the action of CST is somehow linked to a specific aspect of ATR signaling.…”

“…1,2 To avoid such deleterious events, cells have evolved various mechanisms to deal with replication blocks. These include the use of additional proteins to aid passage of the replication fork, 3 the ATR-mediated checkpoint pathway to help prevent fork collapse 4 and the use of backup or dormant origins to ensure that replication forks can traverse all regions of the genome. 5 Telomeres form a natural replication barrier due to their repetitive DNA sequence and chromatin structure.…”

Regulation of Elg1 activity by phosphorylation

“…The activity of the DNA polymerases may be impaired by the presence of secondary structures, bound proteins or DNA lesions; they may also be halted by collisions with other DNA-interacting proteins (such as RNA polymerases, or topoisomerases. 2,3 These encounters may lead to stalling or even collapse of replication forks, creating single-stranded gaps or double-strand breaks (DSBs). In response, cellular mechanisms are activated that arrest cell cycle progression, induce DNA repair or lesion bypass, and restore replication, in what is commonly called the "DNA damage checkpoint" or the "DNA Damage Response" (DDR).…”

Replisome Function During Replicative Stress Is Modulated by Histone H3 Lysine 56 Acetylation Through Ctf4

“…The leadingstrand DNA polymerase-ɛ was recently shown to be integrated into the replisome via an interaction with the GINS complex (Sengupta et al 2013). Furthermore, the DNA polymerasea-primase complex, which initiates DNA synthesis at replication origins and continues to prime Okazaki fragments at the fork, remains associated with the RPC via the Ctf4 trimer, which simultaneously interacts with the GINS complex (Gambus et al 2009;Tanaka et al 2009;Gosnell and Christensen 2011;Simon et al 2014).Cells have evolved different mechanisms to maintain genome integrity under the conditions threatening replication progression (Jossen and Bermejo 2013;Leman and Noguchi 2013). The S-phase checkpoint mediated by MRC1 was initially characterized as a pathway activated by fork stalling and able to both stabilize the replisome and delay cell cycle progression (Elledge 1996;Sancar et al 2004;Labib and De Piccoli 2011).…”

“…Cells have evolved different mechanisms to maintain genome integrity under the conditions threatening replication progression (Jossen and Bermejo 2013;Leman and Noguchi 2013). The S-phase checkpoint mediated by MRC1 was initially characterized as a pathway activated by fork stalling and able to both stabilize the replisome and delay cell cycle progression (Elledge 1996;Sancar et al 2004;Labib and De Piccoli 2011).…”