TY - JOUR
T1 - Human TopBP1 ensures genome integrity during normal S phase
AU - Kim, Ja Eun
AU - McAvoy, Sarah A.
AU - Smith, David I.
AU - Chen, Junjie
PY - 2005/12
Y1 - 2005/12
N2 - Cell cycle checkpoints are essential for maintaining genomic integrity. Human topoisomerase II ding protein 1 (TopBP1) shares sequence similarity with budding yeast Dpb11, fission yeast Rad4/Cut5, and Xenopus Cut5, all of which are required for DNA replication and cell cycle checkpoints. Indeed, we have shown that human TopBP1 participates in the activation of replication checkpoint and DNA damage checkpoints, following hydroxyurea treatment and ionizing radiation. In this study, we address the physiological function of TopBP1 in S phase by using small interfering RNA. In the absence of exogenous DNA damage, TopBP1 is recruited to replicating chromatin. However, TopBP1 does not appear to be essential for DNA replication. TopBP1-deficient cells have increased H2AX phosphorylation and ATM-Chk 2 activation, suggesting the accumulation of DNA double-strand breaks in the absence of TopBP1. This leads to formation of gaps and breaks at fragile sites, 4N accumulation, and aberrant cell division. We propose that the cellular function of TopBP1 is to monitor ongoing DNA replication. By ensuring proper DNA replication, TopBP1 plays a critical role in the maintenance of genomic stability during normal S phase as well as following genotoxic stress.
AB - Cell cycle checkpoints are essential for maintaining genomic integrity. Human topoisomerase II ding protein 1 (TopBP1) shares sequence similarity with budding yeast Dpb11, fission yeast Rad4/Cut5, and Xenopus Cut5, all of which are required for DNA replication and cell cycle checkpoints. Indeed, we have shown that human TopBP1 participates in the activation of replication checkpoint and DNA damage checkpoints, following hydroxyurea treatment and ionizing radiation. In this study, we address the physiological function of TopBP1 in S phase by using small interfering RNA. In the absence of exogenous DNA damage, TopBP1 is recruited to replicating chromatin. However, TopBP1 does not appear to be essential for DNA replication. TopBP1-deficient cells have increased H2AX phosphorylation and ATM-Chk 2 activation, suggesting the accumulation of DNA double-strand breaks in the absence of TopBP1. This leads to formation of gaps and breaks at fragile sites, 4N accumulation, and aberrant cell division. We propose that the cellular function of TopBP1 is to monitor ongoing DNA replication. By ensuring proper DNA replication, TopBP1 plays a critical role in the maintenance of genomic stability during normal S phase as well as following genotoxic stress.
UR - http://www.scopus.com/inward/record.url?scp=28544450740&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28544450740&partnerID=8YFLogxK
U2 - 10.1128/MCB.25.24.10907-10915.2005
DO - 10.1128/MCB.25.24.10907-10915.2005
M3 - Article
C2 - 16314514
AN - SCOPUS:28544450740
SN - 0270-7306
VL - 25
SP - 10907
EP - 10915
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 24
ER -