TY - JOUR

T1 - Versatility of the Mec1ATM/ATR signaling network in mediating resistance to replication, genotoxic, and proteotoxic stresses

AU - Corcoles-Saez, Isaac

AU - Dong, Kangzhen

AU - Cha, Rita S

PY - 2019/6

Y1 - 2019/6

N2 - The ataxia-telangiectasia mutated/ATM and Rad3-related (ATM/ATR) family proteins are evolutionarily conserved serine/threonine kinases best known for their roles in mediating the DNA damage response. Upon activation, ATM/ATR phosphorylate numerous targets to stabilize stalled replication forks, repair damaged DNA, and inhibit cell cycle progression to ensure survival of the cell and safeguard integrity of the genome. Intriguingly, separation of function alleles of the human ATM and MEC1, the budding yeast ATM/ATR, were shown to confer widespread protein aggregation and acute sensitivity to different types of proteotoxic agents including heavy metal, amino acid analogue, and an aggregation-prone peptide derived from the Huntington's disease protein. Further analyses unveiled that ATM and Mec1 promote resistance to perturbation in protein homeostasis via a mechanism distinct from the DNA damage response. In this minireview, we summarize the key findings and discuss ATM/ATR as a multifaceted signalling protein capable of mediating cellular response to both DNA and protein damage.

AB - The ataxia-telangiectasia mutated/ATM and Rad3-related (ATM/ATR) family proteins are evolutionarily conserved serine/threonine kinases best known for their roles in mediating the DNA damage response. Upon activation, ATM/ATR phosphorylate numerous targets to stabilize stalled replication forks, repair damaged DNA, and inhibit cell cycle progression to ensure survival of the cell and safeguard integrity of the genome. Intriguingly, separation of function alleles of the human ATM and MEC1, the budding yeast ATM/ATR, were shown to confer widespread protein aggregation and acute sensitivity to different types of proteotoxic agents including heavy metal, amino acid analogue, and an aggregation-prone peptide derived from the Huntington's disease protein. Further analyses unveiled that ATM and Mec1 promote resistance to perturbation in protein homeostasis via a mechanism distinct from the DNA damage response. In this minireview, we summarize the key findings and discuss ATM/ATR as a multifaceted signalling protein capable of mediating cellular response to both DNA and protein damage.

KW - Ataxia Telangiectasia Mutated Proteins/genetics

KW - DNA Damage

KW - DNA Repair

KW - DNA Replication

KW - Humans

KW - Oxidative Stress

KW - Proteostasis

KW - Signal Transduction

U2 - 10.1007/s00294-018-0920-y

DO - 10.1007/s00294-018-0920-y

M3 - Review article

C2 - 30610294

VL - 65

SP - 657

EP - 661

JO - Current Genetics

JF - Current Genetics

SN - 0172-8083

IS - 3

ER -