Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories

TY - JOUR

T1 - Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories

A1 - Ge,Xin Quan

A1 - Blow,J. Julian

AU - Ge,Xin Quan

AU - Blow,J. Julian

PY - 2010/12/27

Y1 - 2010/12/27

N2 - <p>Replication origins are licensed by loading MCM2-7 hexamers before entry into S phase. However, only similar to 10% of licensed origins are normally used in S phase, with the others remaining dormant. When fork progression is inhibited, dormant origins initiate nearby to ensure that all of the DNA is eventually replicated. In apparent contrast, replicative stress activates ataxia telangiectasia and rad-3-related (ATR) and Chk1 checkpoint kinases that inhibit origin firing. In this study, we show that at low levels of replication stress, ATR/Chk1 predominantly suppresses origin initiation by inhibiting the activation of new replication factories, thereby reducing the number of active factories. At the same time, inhibition of replication fork progression allows dormant origins to initiate within existing replication factories. The inhibition of new factory activation by ATR/Chk1 therefore redirects replication toward active factories where forks are inhibited and away from regions that have yet to start replication. This minimizes the deleterious consequences of fork stalling and prevents similar problems from arising in unreplicated regions of the genome.</p>

AB - <p>Replication origins are licensed by loading MCM2-7 hexamers before entry into S phase. However, only similar to 10% of licensed origins are normally used in S phase, with the others remaining dormant. When fork progression is inhibited, dormant origins initiate nearby to ensure that all of the DNA is eventually replicated. In apparent contrast, replicative stress activates ataxia telangiectasia and rad-3-related (ATR) and Chk1 checkpoint kinases that inhibit origin firing. In this study, we show that at low levels of replication stress, ATR/Chk1 predominantly suppresses origin initiation by inhibiting the activation of new replication factories, thereby reducing the number of active factories. At the same time, inhibition of replication fork progression allows dormant origins to initiate within existing replication factories. The inhibition of new factory activation by ATR/Chk1 therefore redirects replication toward active factories where forks are inhibited and away from regions that have yet to start replication. This minimizes the deleterious consequences of fork stalling and prevents similar problems from arising in unreplicated regions of the genome.</p>

KW - DNA-DAMAGE RESPONSE

KW - S-PHASE

KW - HUMAN-CELLS

KW - REPLICON CLUSTERS

KW - EXCESS MCM2-7

KW - CHECKPOINT

KW - STRESS

KW - CANCER

KW - SITES

KW - ORGANIZATION

U2 - 10.1083/jcb.201007074

DO - 10.1083/jcb.201007074

M1 - Article

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 7

VL - 191

SP - 1285

EP - 1297

ER -