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Review
. 2011 Feb;3(1):4-12.
doi: 10.1093/jmcb/mjq049.

More forks on the road to replication stress recovery

Chris Allen  1 , Amanda K Ashley, Robert Hromas, Jac A Nickoloff
Affiliations
Review

VSports手机版 - More forks on the road to replication stress recovery

Chris Allen et al. J Mol Cell Biol. 2011 Feb.

Abstract

High-fidelity replication of DNA, and its accurate segregation to daughter cells, is critical for maintaining genome stability and suppressing cancer. DNA replication forks are stalled by many DNA lesions, activating checkpoint proteins that stabilize stalled forks. Stalled forks may eventually collapse, producing a broken DNA end. Fork restart is typically mediated by proteins initially identified by their roles in homologous recombination repair of DNA double-strand breaks (DSBs). In recent years, several proteins involved in DSB repair by non-homologous end joining (NHEJ) have been implicated in the replication stress response, including DNA-PKcs, Ku, DNA Ligase IV-XRCC4, Artemis, XLF and Metnase. It is currently unclear whether NHEJ proteins are involved in the replication stress response through indirect (signaling) roles, and/or direct roles involving DNA end joining. Additional complexity in the replication stress response centers around RPA, which undergoes significant post-translational modification after stress, and RAD52, a conserved HR protein whose role in DSB repair may have shifted to another protein in higher eukaryotes, such as BRCA2, but retained its role in fork restart. Most cancer therapeutic strategies create DNA replication stress. Thus, it is imperative to gain a better understanding of replication stress response proteins and pathways to improve cancer therapy. VSports手机版.

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Figures

Figure 1
Figure 1
Key proteins and pathways in the replication stress response network. Black arrows/bars indicate activation/suppression pathways or interactions between proteins; red arrows indicate some of the known phosphorylation events by indicated PIKs. Note that several proteins, such as RPA and ATR, have roles in more than one pathway in this network.
Figure 2
Figure 2
Replication-associated HR can occur with or without genetic rearrangement. A lesion in one repeat (blue) blocks replication which restarts by template switching in register (A), an undetectable error-free HR event, or out of register (B) which can produce detectable rearrangements. After the out of register template (red) is copied, a second template switch yields repeat deletion (solid arrow in B gives intermediate in C), or gene conversion (dashed arrow in B gives intermediate in D). Similar events can occur with blocked leading or lagging strand. The heteroduplex intermediates in C and D are subject to mismatch repair which can fix (make permanent) the genetic changes or restore the parental configuration, or heteroduplex may go unrepaired and segregate during the next mitosis, producing one daughter cell with a deletion or gene conversion and one daughter cell with the original parental configuration. Note that lesion is not repaired; these are HR-mediated lesion bypass mechanisms.
Figure 3
Figure 3
Break-induced replication rescues collapsed forks. A DSE at a collapsed fork can invade the sister chromatid and DNA synthesis can extend the broken end to the end of the chromosome. Synthesis of the second strand completes the replication process.
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