Activation of ATR-related protein kinase upon DNA damage recognition

TY - JOUR

T1 - Activation of ATR-related protein kinase upon DNA damage recognition

AU - Ma, Minh

AU - Rodriguez, Anibian

AU - Sugimoto, Katsunori

N1 - Funding Information: This work was supported by Grant GM120730 (KS) from National Institute of Health ( http://www.nih.gov ). Publisher Copyright: © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Chromosomes are constantly damaged by exogenous and endogenous factors. To cope with DNA damage, eukaryotic cells are equipped with three phosphatidylinositol 3-kinase-related kinases (PIKKs), such as ATM, ATR, and DNA-PK. PIKKs are structurally related to phosphatidylinositol 3-kinase (lipid kinase), however possess protein kinase activities. The Mre11–Rad50–Nbs1 and the Ku complex interact with and activate ATM and DNA-PKcs at double-stranded DNA breaks (DSBs), respectively. In contrast, ATR responds to various types of DNA lesions by interacting with replication protein A (RPA)-covered single-stranded DNA (ssDNA). Several lines of evidence have established a model in which ATR is activated by interacting with ATR activating proteins including TopBP1 and ETAA1 at DNA lesions in humans, yet the interaction of ATR with RPA-covered ssDNA does not result in ATR activation. In budding yeast, the Mec1–Ddc2 complex (Mec1–Ddc2) corresponds to ATR–ATRIP. Similar to ATR, Mec1 activation is accomplished by interactions with Mec1 activating proteins, which are Ddc1, Dpb11 (TopBP1 homolog) and Dna2. However, recent studies provide results supporting the idea that Mec1ATR is also activated by interacting with RPA-covered ssDNA tracts. These observations suggest that all the ATM, ATR, DNA-PK family proteins can be activated immediately upon DNA damage recognition.

AB - Chromosomes are constantly damaged by exogenous and endogenous factors. To cope with DNA damage, eukaryotic cells are equipped with three phosphatidylinositol 3-kinase-related kinases (PIKKs), such as ATM, ATR, and DNA-PK. PIKKs are structurally related to phosphatidylinositol 3-kinase (lipid kinase), however possess protein kinase activities. The Mre11–Rad50–Nbs1 and the Ku complex interact with and activate ATM and DNA-PKcs at double-stranded DNA breaks (DSBs), respectively. In contrast, ATR responds to various types of DNA lesions by interacting with replication protein A (RPA)-covered single-stranded DNA (ssDNA). Several lines of evidence have established a model in which ATR is activated by interacting with ATR activating proteins including TopBP1 and ETAA1 at DNA lesions in humans, yet the interaction of ATR with RPA-covered ssDNA does not result in ATR activation. In budding yeast, the Mec1–Ddc2 complex (Mec1–Ddc2) corresponds to ATR–ATRIP. Similar to ATR, Mec1 activation is accomplished by interactions with Mec1 activating proteins, which are Ddc1, Dpb11 (TopBP1 homolog) and Dna2. However, recent studies provide results supporting the idea that Mec1ATR is also activated by interacting with RPA-covered ssDNA tracts. These observations suggest that all the ATM, ATR, DNA-PK family proteins can be activated immediately upon DNA damage recognition.

KW - Checkpoint

KW - DNA replication

KW - Ddc2

KW - Mec1

KW - Replication protein A

KW - Single-stranded DNA

UR - http://www.scopus.com/inward/record.url?scp=85073938835&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073938835&partnerID=8YFLogxK

U2 - 10.1007/s00294-019-01039-w

DO - 10.1007/s00294-019-01039-w

M3 - Review article

C2 - 31624858

SN - 0172-8083

VL - 66

SP - 327

EP - 333

JO - Current Genetics

JF - Current Genetics

IS - 2

ER -