TY - JOUR

T1 - Pathways for maintenance of telomeres and common fragile sites during DNA replication stress

AU - Özer, Özgün

AU - Hickson, Ian D.

PY - 2018

Y1 - 2018

N2 - Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA replication stress due to their inherently 'difficult-to-replicate' nature. Indeed, it appears that these regions sometimes fail to complete DNA replication within the period of interphase when cells are exposed to DNA replication stress. Under these conditions, cells use a salvage pathway, termed 'mitoticDNArepair synthesis (MiDAS)', to complete DNA synthesis in the early stages of mitosis. If MiDAS fails, the ensuing mitotic errors threaten genome integrity and cell viability. Recent studies have provided an insight into howMiDAS helps cells to counteractDNAreplication stress. However, our understanding of the molecular mechanisms and regulation of MiDAS remain poorly defined. Here, we provide an overview of how DNA replication stress triggers MiDAS, with an emphasis on how common fragile sites and telomeres are maintained. Furthermore, we discuss how a better understanding of MiDAS might reveal novel strategies to target cancer cells that maintain viability in the face of chronic oncogene-induced DNA replication stress.

AB - Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA replication stress due to their inherently 'difficult-to-replicate' nature. Indeed, it appears that these regions sometimes fail to complete DNA replication within the period of interphase when cells are exposed to DNA replication stress. Under these conditions, cells use a salvage pathway, termed 'mitoticDNArepair synthesis (MiDAS)', to complete DNA synthesis in the early stages of mitosis. If MiDAS fails, the ensuing mitotic errors threaten genome integrity and cell viability. Recent studies have provided an insight into howMiDAS helps cells to counteractDNAreplication stress. However, our understanding of the molecular mechanisms and regulation of MiDAS remain poorly defined. Here, we provide an overview of how DNA replication stress triggers MiDAS, with an emphasis on how common fragile sites and telomeres are maintained. Furthermore, we discuss how a better understanding of MiDAS might reveal novel strategies to target cancer cells that maintain viability in the face of chronic oncogene-induced DNA replication stress.

KW - Alternative lengthening of telomeres

KW - Cancer

KW - Common fragile sites

KW - Homologous recombination

KW - RAD52

U2 - 10.1098/rsob.180018

DO - 10.1098/rsob.180018

M3 - Review

C2 - 29695617

AN - SCOPUS:85055413808

VL - 8

JO - Open Biology

JF - Open Biology

SN - 2046-2441

IS - 4

M1 - 180018

ER -