Replication Catastrophe: When a Checkpoint Fails because of Exhaustion

TY - JOUR

T1 - Replication Catastrophe

T2 - When a Checkpoint Fails because of Exhaustion

AU - Toledo, Luis

AU - Neelsen, Kai John

AU - Lukas, Jiri

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2017/6/15

Y1 - 2017/6/15

N2 - Proliferating cells rely on the so-called DNA replication checkpoint to ensure orderly completion of genome duplication, and its malfunction may lead to catastrophic genome disruption, including unscheduled firing of replication origins, stalling and collapse of replication forks, massive DNA breakage, and, ultimately, cell death. Despite many years of intensive research into the molecular underpinnings of the eukaryotic replication checkpoint, the mechanisms underlying the dismal consequences of its failure remain enigmatic. A recent development offers a unifying model in which the replication checkpoint guards against global exhaustion of rate-limiting replication regulators. Here we discuss how such a mechanism can prevent catastrophic genome disruption and suggest how to harness this knowledge to advance therapeutic strategies to eliminate cancer cells that inherently proliferate under increased DNA replication stress.

AB - Proliferating cells rely on the so-called DNA replication checkpoint to ensure orderly completion of genome duplication, and its malfunction may lead to catastrophic genome disruption, including unscheduled firing of replication origins, stalling and collapse of replication forks, massive DNA breakage, and, ultimately, cell death. Despite many years of intensive research into the molecular underpinnings of the eukaryotic replication checkpoint, the mechanisms underlying the dismal consequences of its failure remain enigmatic. A recent development offers a unifying model in which the replication checkpoint guards against global exhaustion of rate-limiting replication regulators. Here we discuss how such a mechanism can prevent catastrophic genome disruption and suggest how to harness this knowledge to advance therapeutic strategies to eliminate cancer cells that inherently proliferate under increased DNA replication stress.

KW - Animals

KW - Cell Death

KW - Cell Proliferation

KW - DNA

KW - DNA Damage

KW - DNA Repair

KW - DNA Replication

KW - Genomic Instability

KW - Humans

KW - Neoplasms

KW - Replication Protein A

KW - Journal Article

KW - Review

U2 - 10.1016/j.molcel.2017.05.001

DO - 10.1016/j.molcel.2017.05.001

M3 - Review

C2 - 28622519

SN - 1097-2765

VL - 66

SP - 735

EP - 749

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -