Regulation of Structure-Specific Endonucleases in Replication Stress.

Seong Min Kim,Susan L Forsburg

doi:10.3390/genes9120634

Abstract

Replication stress results in various forms of aberrant replication intermediates that need to be resolved for faithful chromosome segregation. Structure-specific endonucleases (SSEs) recognize DNA secondary structures rather than primary sequences and play key roles during DNA repair and replication stress. Holliday junction resolvase MUS81 (methyl methane sulfonate (MMS), and UV-sensitive protein 81) and XPF (xeroderma pigmentosum group F-complementing protein) are a subset of SSEs that resolve aberrant replication structures. To ensure genome stability and prevent unnecessary DNA breakage, these SSEs are tightly regulated by the cell cycle and replication checkpoints. We discuss the regulatory network that control activities of MUS81 and XPF and briefly mention other SSEs involved in the resolution of replication intermediates.

Highlights

The DNA replication fork is sensitive to a variety of intrinsic and extrinsic stresses.Endogenous blocks include collisions with transcription apparatus, natural pausing sites, and unusualDNA structures or sequences
A recent study showed that the pleiotropic serine/threonine kinase CK2 kinase is able to in late-G2/mitosis and upon mild replication stress to promote its association with EME1 and scaffold protein SLX4, another stimulator of MUS81 activity [60]
MUS81-EME1 and Xeroderma pigmentosum group F complementing protein (XPF)-excision repair cross-complementing group 1 (ERCC1), along with the scaffold protein SLX4, are the most well-characterized specific endonucleases (SSEs) to be responsible for processing replication intermediates, a few other SSEs have been noted to be important in dealing with replication stress

Summary

Introduction

The DNA replication fork is sensitive to a variety of intrinsic and extrinsic stresses (reviewed in [1,2]). Replication stress can result in accumulation of single stranded DNA, chromosome breaks, and rearrangements, which are deleterious to the cell (reviewed in [1,2]). It may generate aberrant intermediates including DNA secondary structures, DNA lesions, and protein-DNA complexes (reviewed in [4]). GEN1 in human cells is able to access chromosomes only after nuclear membrane breakdown during replication intermediates but cell cycle-dependent regulation of these SSEs are not well characterized mitosis [25]. 2. Mus81-Essential Meiotic Endonuclease 1 (Schizosaccharomyces pombe)/Mus81-Mms contribute to processing replication intermediates but cell cycle-dependent regulation of these SSEs (Saccharomyces cerevisiae)/MUS81-EME1/2 (Human) are not well characterized (reviewed in [8]).

Mus81-Essential

Regulation of Mus81 by Cell Cycle Kinases

Mus81 is Regulated by the Replication Checkpoint during Replication Stress

Other Regulators of Mus81 Recruitment and Activity

Other Structure-Specific Endonuclease in Replication Stress

Concluding Remarks