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

  title={MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways},
  author={Zhenkun Lou and Katherine Minter-Dykhouse and Xianglin Wu and Junjie Chen},
Forkhead-homology-associated (FHA) domains function as protein–protein modules that recognize phosphorylated serine/threonine motifs. 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-domain-containing protein—mediator of DNA damage checkpoint protein 1 (MDC1; previously known… 

The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator

X-ray structures of free and complexed MDC1 FHA domain reveal a ‘head-to-tail’ dimerization mechanism that is closely related to that seen in pre-activated forms of the Chk2 DNA damage kinase, and which both positively and negatively influences Mdc1 F HA domain-mediated interactions in human cells prior to and following DNA damage.

ID3 regulates the MDC1-mediated DNA damage response in order to maintain genome stability

This study uncovers an ID3-dependent mechanism of recruitment of MDC1 to DNA damage sites and suggests that the ID3–MDC1 interaction is crucial for DDR.

14-3-3 Proteins , FHA Domains and BRCT Domains in the DNA Damage Response Citation

This review considers how substrate phsophorylation together with BRCT domains, FHA domains and 14-3-3 proteins function to regulate ionizing radiationinduced nuclear foci and help to establish the G2/M checkpoint.

Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage

It is shown that MDC1 is phosphorylated on a cluster of conserved repeat motifs by casein kinase 2 (CK2), and that these CK2‐targeted motifs in M DC1 are required to mediate NBS1 association with chromatin‐flanking sites of unrepaired DSBs.

The DNA Damage Response Mediator MDC1 Directly Interacts with the Anaphase-promoting Complex/Cyclosome*

A link between the cellular response to DNA damage and cell cycle regulation is revealed, suggesting that MDC1, known to have a role in checkpoint regulation, executes part of this role by binding the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that controls the cell cycle.

Regulatory motifs in Chk1

It is shown here that Chk1 homologs possess a kinase-associated 1 (KA1) domain that possesses residues previously implicated in Chk 1 auto-inhibition, and all Chk2 homologys have a small and highly conserved C-terminal extension (CTE domain), which may provide alternative targets to the ATP-binding pocket on which to dock Ch k1 inhibitors as anticancer therapeutics.

The Plk1 Polo Box Domain Mediates a Cell Cycle and DNA Damage Regulated Interaction with Chk2

It is shown that the interaction between Chk2 and Plk1 is cellcycle-regulated, with a peak in mitosis, and potential mechanisms for interaction and inter-regulation of these two protein kinases are identified.

Accumulation of Pax2 Transactivation Domain Interaction Protein (PTIP) at Sites of DNA Breaks via RNF8-dependent Pathway Is Required for Cell Survival after DNA Damage*

This study showed that recruitment of PTIP to damaged chromatin depends on DNA damage signaling proteins γH2AX·MDC1·RNF8, which in turn facilitates sustained localization of PA1 (PTIP-associated protein 1) to sites of DNA break.



Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway

Results suggest that Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway and might not only delay mitotic entry, but also increase the capacity of cultured cells to survive after treatment with γ-radiation or with the topoisomerase-I inhibitor topotecan.

Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53.

In response to DNA damage, Chk2/hCds1 stabilizes the p53 tumor suppressor protein leading to cell cycle arrest in G(1), suggesting that it arrests cells in G (2) in response toDNA damage.

Chk2 Activation and Phosphorylation-Dependent Oligomerization

It is shown here that autophosphorylation of Chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably ATM or ATR, and that Chk 2 oligomerization regulates Chk1 activation, signal amplification, and transduction in DNA damage checkpoint pathways.

The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis

A functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2) and Cdc25A is reported, and this mechanism in controlling the S-phase checkpoint is identified as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.

Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1

Threonine 68 of Cds1 is the preferred site of phosphorylation by ATM in vitro, and is the principal irradiation-induced site ofosphorylation in vivo, which is demonstrated by the failure of a mutant, non-phosphorylatable form of CDS1 to be fully activated, and by its reduced ability to induce G1 arrest in response to ionising radiation.

Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.

Chk2, the mammalian homolog of the Saccharomyces cerevisiae Rad53 and Schizosac charomyces pombe Cds1 protein kinases required for the DNA damage and replication checkpoints, was identified and phosphorylated and activated in response to replication blocks and DNA damage.

Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation.

It is shown that the ATM protein kinase directly phosphorylates T68 within the SQ/TQ-rich domain of Chk2 in vitro and that T68 is phosphorylated in vivo in response to IR in an ATM-dependent manner.

DNA damage-induced activation of p53 by the checkpoint kinase Chk2.

Chk2 directly phosphorylated p53 on serine 20, which is known to interfere with Mdm2 binding, and provides a mechanism for increased stability of p53 by prevention of ubiquitination in response to DNA damage.