TY - JOUR
T1 - Yet another job for Dna2
T2 - Checkpoint activation
AU - Wanrooij, Paulina H.
AU - Burgers, Peter M.
N1 - Funding Information:
Work in the laboratory of P.B. is supported by grants GM032431 and GM083970 from the National Institutes of Health . P.W. is funded by the Emil Aaltonen Foundation and the Swedish Cultural Foundation in Finland .
Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - Mec1 (ATR in humans) is the principal kinase responsible for checkpoint activation in response to replication stress and DNA damage in Saccharomyces cerevisiae. Checkpoint initiation requires stimulation of Mec1 kinase activity by specific activators. The complexity of checkpoint initiation in yeast increases with the complexity of chromosomal states during the different phases of the cell cycle. In G1 phase, the checkpoint clamp 9-1-1 is both necessary and sufficient for full activation of Mec1 kinase whereas in G2/M, robust checkpoint function requires both 9-1-1 and the replisome assembly protein Dpb11 (human TopBP1). A third activator, Dna2, is employed specifically during S phase to stimulate Mec1 kinase and to initiate the replication checkpoint. Dna2 is an essential nuclease-helicase that is required for proper Okazaki fragment maturation, for double-strand break repair, and for protecting stalled replication forks. Remarkably, all three Mec1 activators use an unstructured region of the protein, containing two critically important aromatic residues, in order to activate Mec1. A role for these checkpoint activators in channeling aberrant replication structures into checkpoint complexes is discussed.
AB - Mec1 (ATR in humans) is the principal kinase responsible for checkpoint activation in response to replication stress and DNA damage in Saccharomyces cerevisiae. Checkpoint initiation requires stimulation of Mec1 kinase activity by specific activators. The complexity of checkpoint initiation in yeast increases with the complexity of chromosomal states during the different phases of the cell cycle. In G1 phase, the checkpoint clamp 9-1-1 is both necessary and sufficient for full activation of Mec1 kinase whereas in G2/M, robust checkpoint function requires both 9-1-1 and the replisome assembly protein Dpb11 (human TopBP1). A third activator, Dna2, is employed specifically during S phase to stimulate Mec1 kinase and to initiate the replication checkpoint. Dna2 is an essential nuclease-helicase that is required for proper Okazaki fragment maturation, for double-strand break repair, and for protecting stalled replication forks. Remarkably, all three Mec1 activators use an unstructured region of the protein, containing two critically important aromatic residues, in order to activate Mec1. A role for these checkpoint activators in channeling aberrant replication structures into checkpoint complexes is discussed.
KW - ATR
KW - Dna2
KW - Mec1
KW - Nuclease
KW - Replication checkpoint
UR - http://www.scopus.com/inward/record.url?scp=84938485356&partnerID=8YFLogxK
U2 - 10.1016/j.dnarep.2015.04.009
DO - 10.1016/j.dnarep.2015.04.009
M3 - Article
C2 - 25956863
AN - SCOPUS:84938485356
VL - 32
SP - 17
EP - 23
JO - DNA Repair
JF - DNA Repair
SN - 1568-7864
ER -