MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways

Zhenkun Lou, Katherine Minter-Dykhouse, Xianglin Wu, Junjie Chen

Research output: Contribution to journalArticle

264 Citations (Scopus)

Abstract

Forkhead-homology-associated (FHA) domains function as protein-protein modules that recognize phosphorylated serine/threonine motifs1-5. Interactions between FHA domains and phosphorylated proteins are thought to have essential roles in the transduction of DNA damage signals; however, it is unclear how FHA-domain-containing proteins participate in mammalian DNA damage responses. Here we report that a FHA-domaincontaining protein - mediator of DNA damage checkpoint protein 1 (MDC1; previously known as KIAA0170) - is involved in DNA damage responses. MDC1 localizes to sites of DNA breaks and associates with CHK2 after DNA damage. This association is mediated by the MDC1 FHA domain and the phosphorylated Thr 68 of CHK2. Furthermore, MDC1 is phosphorylated in an ATM/CHK2-dependent manner after DNA damage, suggesting that MDC1 may function in the ATM-CHK2 pathway. Consistent with this hypothesis, suppression of MDC1 expression results in defective S-phase checkpoint and reduced apoptosis in response to DNA damage, which can be restored by the expression of wildtype MDC1 but not MDC1 with a deleted FHA domain. Suppression of MDC1 expression results in decreased p53 stabilization in response to DNA damage. These results suggest that MDC1 is recruited through its FHA domain to the activated CHK2, and has a critical role in CHK2-mediated DNA damage responses.

Original languageEnglish (US)
Pages (from-to)957-961
Number of pages5
JournalNature
Volume421
Issue number6926
DOIs
StatePublished - Feb 27 2003

Fingerprint

DNA Damage
Proteins
S Phase Cell Cycle Checkpoints
DNA Breaks
Threonine
Serine
Apoptosis

ASJC Scopus subject areas

  • General

Cite this

MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. / Lou, Zhenkun; Minter-Dykhouse, Katherine; Wu, Xianglin; Chen, Junjie.

In: Nature, Vol. 421, No. 6926, 27.02.2003, p. 957-961.

Research output: Contribution to journalArticle

Lou, Z, Minter-Dykhouse, K, Wu, X & Chen, J 2003, 'MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways', Nature, vol. 421, no. 6926, pp. 957-961. https://doi.org/10.1038/nature01447
Lou, Zhenkun ; Minter-Dykhouse, Katherine ; Wu, Xianglin ; Chen, Junjie. / MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. In: Nature. 2003 ; Vol. 421, No. 6926. pp. 957-961.
@article{1a8ca5f272b44cab9b74eea60dd85030,
title = "MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways",
abstract = "Forkhead-homology-associated (FHA) domains function as protein-protein modules that recognize phosphorylated serine/threonine motifs1-5. Interactions between FHA domains and phosphorylated proteins are thought to have essential roles in the transduction of DNA damage signals; however, it is unclear how FHA-domain-containing proteins participate in mammalian DNA damage responses. Here we report that a FHA-domaincontaining protein - mediator of DNA damage checkpoint protein 1 (MDC1; previously known as KIAA0170) - is involved in DNA damage responses. MDC1 localizes to sites of DNA breaks and associates with CHK2 after DNA damage. This association is mediated by the MDC1 FHA domain and the phosphorylated Thr 68 of CHK2. Furthermore, MDC1 is phosphorylated in an ATM/CHK2-dependent manner after DNA damage, suggesting that MDC1 may function in the ATM-CHK2 pathway. Consistent with this hypothesis, suppression of MDC1 expression results in defective S-phase checkpoint and reduced apoptosis in response to DNA damage, which can be restored by the expression of wildtype MDC1 but not MDC1 with a deleted FHA domain. Suppression of MDC1 expression results in decreased p53 stabilization in response to DNA damage. These results suggest that MDC1 is recruited through its FHA domain to the activated CHK2, and has a critical role in CHK2-mediated DNA damage responses.",
author = "Zhenkun Lou and Katherine Minter-Dykhouse and Xianglin Wu and Junjie Chen",
year = "2003",
month = "2",
day = "27",
doi = "10.1038/nature01447",
language = "English (US)",
volume = "421",
pages = "957--961",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "6926",

}

TY - JOUR

T1 - MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways

AU - Lou, Zhenkun

AU - Minter-Dykhouse, Katherine

AU - Wu, Xianglin

AU - Chen, Junjie

PY - 2003/2/27

Y1 - 2003/2/27

N2 - Forkhead-homology-associated (FHA) domains function as protein-protein modules that recognize phosphorylated serine/threonine motifs1-5. Interactions between FHA domains and phosphorylated proteins are thought to have essential roles in the transduction of DNA damage signals; however, it is unclear how FHA-domain-containing proteins participate in mammalian DNA damage responses. Here we report that a FHA-domaincontaining protein - mediator of DNA damage checkpoint protein 1 (MDC1; previously known as KIAA0170) - is involved in DNA damage responses. MDC1 localizes to sites of DNA breaks and associates with CHK2 after DNA damage. This association is mediated by the MDC1 FHA domain and the phosphorylated Thr 68 of CHK2. Furthermore, MDC1 is phosphorylated in an ATM/CHK2-dependent manner after DNA damage, suggesting that MDC1 may function in the ATM-CHK2 pathway. Consistent with this hypothesis, suppression of MDC1 expression results in defective S-phase checkpoint and reduced apoptosis in response to DNA damage, which can be restored by the expression of wildtype MDC1 but not MDC1 with a deleted FHA domain. Suppression of MDC1 expression results in decreased p53 stabilization in response to DNA damage. These results suggest that MDC1 is recruited through its FHA domain to the activated CHK2, and has a critical role in CHK2-mediated DNA damage responses.

AB - Forkhead-homology-associated (FHA) domains function as protein-protein modules that recognize phosphorylated serine/threonine motifs1-5. Interactions between FHA domains and phosphorylated proteins are thought to have essential roles in the transduction of DNA damage signals; however, it is unclear how FHA-domain-containing proteins participate in mammalian DNA damage responses. Here we report that a FHA-domaincontaining protein - mediator of DNA damage checkpoint protein 1 (MDC1; previously known as KIAA0170) - is involved in DNA damage responses. MDC1 localizes to sites of DNA breaks and associates with CHK2 after DNA damage. This association is mediated by the MDC1 FHA domain and the phosphorylated Thr 68 of CHK2. Furthermore, MDC1 is phosphorylated in an ATM/CHK2-dependent manner after DNA damage, suggesting that MDC1 may function in the ATM-CHK2 pathway. Consistent with this hypothesis, suppression of MDC1 expression results in defective S-phase checkpoint and reduced apoptosis in response to DNA damage, which can be restored by the expression of wildtype MDC1 but not MDC1 with a deleted FHA domain. Suppression of MDC1 expression results in decreased p53 stabilization in response to DNA damage. These results suggest that MDC1 is recruited through its FHA domain to the activated CHK2, and has a critical role in CHK2-mediated DNA damage responses.

UR - http://www.scopus.com/inward/record.url?scp=0037468232&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037468232&partnerID=8YFLogxK

U2 - 10.1038/nature01447

DO - 10.1038/nature01447

M3 - Article

C2 - 12607004

AN - SCOPUS:0037468232

VL - 421

SP - 957

EP - 961

JO - Nature

JF - Nature

SN - 0028-0836

IS - 6926

ER -