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Mechanisms of Oncogene-Induced Replication Stress: Jigsaw Falling Into Place

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Mechanisms of Oncogene-Induced Replication Stress: Jigsaw Falling Into Place Published OnlineFirst April 13, 2018; DOI: 10.1158/2159-8290.CD-17-1461 REVIEW Mechanisms of Oncogene-Induced Replication Stress: Jigsaw Falling into Place Panagiotis Kotsantis1, Eva Petermann2, and Simon J. Boulton1 ABSTRACT Oncogene activation disturbs cellular processes and accommodates a complex landscape of changes in the genome that contribute to genomic instability, which accelerates mutation rates and promotes tumorigenesis. Part of this cellular turmoil involves deregu- lation of physiologic DNA replication, widely described as replication stress. Oncogene-induced rep- lication stress is an early driver of genomic instability and is attributed to a plethora of factors, most notably aberrant origin firing, replication–transcription collisions, reactive oxygen species, and defec- tive nucleotide metabolism. Significance: Replication stress is a fundamental step and an early driver of tumorigenesis and has been associated with many activated oncogenes. Deciphering the mechanisms that contribute to the replica- tion stress response may provide new avenues for targeted cancer treatment. In this review, we discuss the latest findings on the DNA replication stress response and examine the various mechanisms through which activated oncogenes induce replication stress. Cancer Discov; 8(5); 1–19. ©2018 AACR. INTRODUCTION consists of two stages: licensing and initiation (reviewed in ref. 7). In eukaryotic cells, the licensing stage is restricted Genomic instability (GIN) has been highlighted as a driv­ during late mitosis and G ­phase when thousands of replica­ ing force of tumorigenesis by Hanahan and Weinberg in 1 tion origins are established along the genome and ensures their celebrated “Hallmarks of Cancer” article (1). GIN can that DNA replication occurs only once per cell cycle. For an result from changes in the number or structure of chromo­ origin to form, the origin recognition complex (ORC) binds somes (chromosomal instability), changes in the number of at the origin site and recruits CDT1 and CDC6, which in oligonucleotide repeats in microsatellite sequences (micro­ turn facilitate loading of the minichromosome maintenance satellite instability), or base pair mutations, all of which are 2–7 (MCM2­7) helicases to form the prereplicative complex associated with activated oncogenes. Deregulation of DNA (pre­RC; Fig. 1A). replication, known as replication stress (RS), is linked to Cell­cycle progression is controlled by cyclin­dependent GIN and is increased during the early steps of carcinogene­ kinases (CDK) and the retinoblastoma/E2F pathway. CDK sis (2–4). In particular, RS has been associated with chromo­ activity depends on binding to their regulatory subunits, somal instability (5) as well as activation of the APOBEC3 cyclins, whose levels are regulated throughout the cell cycle family of deaminases (6), which increase the mutagenic load by the anaphase­promoting complex/cyclosome (APC/C). that fuels tumorigenesis. In this review, we cover the latest APC/C activity is high from late M to late G ­phase; hence, findings on the RS response and discuss in detail the various 1 CDK activity oscillates accordingly, being low during G mechanisms through which oncogenes induce RS. 1 and high during S/G2­phases. Mitogenic signaling by RAS triggers CYCLIN D/CDK4 to phosphorylate retinoblastoma DNA REPLICATION (RB), which renders it inactive, thus alleviating its inhibitory effect on the E2F family of transcription activators. E2F pro­ DNA replication ensures the precise duplication of DNA teins promote expression of CYCLIN A and E, among other during each cell cycle. It is a tightly regulated process that key S­phase genes, which upon binding to CDK2 during G1/ S­phase partake in promoting entry into the S­phase. Replication initiation occurs as the cell proceeds into the 1The Francis Crick Institute, London, United Kingdom. 2Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, S­phase and requires the concerted action of CDK2 and DBF4/ United Kingdom. DRF1–dependent CDC7 kinases, which phosphorylate the Corresponding Author: Panagiotis Kotsantis, The Francis Crick Institute, pre­RC, allowing recruitment of CDC45 and the GINS com­ 1 Midland Road, London, NW1 1AT, United Kingdom. Phone: 44-203-796- plex, and leads to the activation of the replicative helicase 3297; E-mail: [email protected] (CMG complex). Once this occurs, a replication bubble is doi: 10.1158/2159-8290.CD-17-1461 formed, and replication forks proceed bidirectionally from the ©2018 American Association for Cancer Research. origin (Fig. 1A). Under normal conditions, an excess of origins MAY 2018 CANCER DISCOVERY | OF1 Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst April 13, 2018; DOI: 10.1158/2159-8290.CD-17-1461 REVIEW Kotsantis et al. A GINS GINS MCM MCM CDC45 CDC45 P P TRESLIN TRESLIN P P CDC7 E2F active Cyclin A CDK2 P RB E2F Cyclin E CDK2 PCNA PCNA RFC RFC Polε Polδ MCM MCM S CYCLIN D CDK4 Polδ Polε ↓ APC/C RFC RFC ↑ APC/C ↑ CDK CDK G1 ↓ RB E2F E2F inactive G2 M CDT1 CDT1 MCM ORC MCM ORC CDC6 CDC6 PCNA B Polε MCM RPA RPA Polδ RPA RPA 9-1-1 RPA γH2AX γH2AX RAD17 TOPBP1 ETAA1 S ATR ATRIP G1 TIMELESS TIPIN CLASPIN G2 M Cell-cycle arrest Homologous recombination Repriming CHK1 Template switching Translesion synthesis Dormant origin firing Break-induced replication SMARCAL1, BLM, Inhibited late origin firing WRN, PARP1, BRCA2, RAD51, Fork restart FANCM, FBH1 MRE11, EXO1, DNA2 Fork stabilization Fork regression Senescence MUS81–EME1, XPF–ERCC1, Fork collapse DSBs EXO1, SLX4 Figure 1. DNA replication and RS response. A, In late mitosis and throughout G1-phase, the prereplicative complex comprised of the ORC complex, CDC6, and CDT1 is recruited to replication origins to facilitate loading of the MCM2-7 complex. During G1-phase, retinoblastoma (RB) is bound to E2F, rendering it inactive. Phosphorylation of RB by the CYCLIN D–CDK4 complex alleviates its inhibitory effect on E2F. APC/C activity is high from late M- to late G1-phase regulating CDK activity. Upon entry in the S-phase, APC/C is inhibited and CDKs are activated throughout S, G2, and early M-phase. CDKs form complexes with E2F-regulated cyclins that collaborate with CDC7 to phosphorylate TRESLIN and MCM2-7 complex, activating the CMG (CDC45- MCM2-7-GINS) helicase complex. Simultaneously, clamp loader RFC and sliding clamp PCNA are recruited and enable polymerases δ and ε to initiate replication in the lagging and leading strands, respectively. B, When a replication fork is stalled, ssDNA is generated as the CMG complex unwinds DNA. ssDNA binds RPA that recruits ATR (through ATRIP), RAD17–RFC, and 9-1-1 complexes at the stalled fork. ATR is then activated by TOPBP1/RAD17/ 9-1-1 and ETAA1 and phosphorylates H2AX, while through TIMELESS/TIPIN/CLASPIN phoshoprylates CHK1. CHK1 then organizes the RS response by arresting the cell cycle, inhibiting new origin firing, enabling dormant origin firing and stabilizing the fork, which can then be reversed by various proteins in a chicken foot structure. An unprotected reversed fork is susceptible to nucleolytic degradation by MRE11, EXO1, and DNA2. A stalled fork can restart through homologous recombination, repriming, template switching, translesion synthesis, or break-induced replication. Alternatively, it will collapse into DSBs by the combined activity of MUS81–EME1, XPF–ERCC1, EXO1, and SLX4 that will drive the cell to senescence. OF2 | CANCER DISCOVERY MAY 2018 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst April 13, 2018; DOI: 10.1158/2159-8290.CD-17-1461 How Do Oncogenes Induce Replication Stress REVIEW is licensed but only a small number of them become activated, In order to complete DNA replication in response to any with the remaining dormant origins reserved as a backup. disturbance, CHK1 inhibits origin firing at new replication factories (late origins), while at the same time allowing the firing of dormant origins within active replication factories THE DNA RS RESPONSE that experience stress (Fig. 1B; refs. 14, 15). Replication is susceptible to impediments in DNA caused by both exogenous and endogenous DNA­damaging agents and Replication Fork Stabilization and Reversal by the intrinsic properties of certain DNA sequences to adopt Stabilization of the replication fork has long been consid­ secondary structures. In particular, fork progression can be ered a CHK1 response to RS, protecting it from deleterious hindered due to interference with the transcription machinery, nucleolytic processing. This view has been challenged recently torsional stress or non­B DNA structures (cruciforms, hair­ by evidence from yeast, showing that fork stability is retained pins, trinucleotide repeats, R­loops, G­quadruplexes). in the absence of checkpoint kinases (16). In addition, a SILAC­iPOND study in human cells revealed ATR to be The ATR/CHK1 Pathway responsible for fork but not replisome stability in response to In response to RS, the cell initiates a DNA damage response RS and that ATR protects the fork from various forms of col­ (DDR) with the aim of resolving the damage or DNA second­ lapse (17). Notably, RS at an active fork triggers accumulation ary structures and restoring fork progression (reviewed in ref. of homologous recombination proteins, whereas RS arising 8). During replication fork stalling,
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