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

TY - JOUR

T1 - The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator.

AU - Jungmichel, Stephanie

AU - Clapperton, Julie A

AU - Janette, Lloyd

AU - Hari, Flurina J

AU - Spycher, Christoph

AU - Pavic, Lucijana

AU - Li, Jiejin

AU - Haire, Lesley F

AU - Bonalli, Mario

AU - Larsen, Dorthe Helena

AU - Lukas, Claudia

AU - Lukas, Jiri

AU - MacMillan, Derek

AU - Nielsen, Michael Lund

AU - Stucki, Manuel

AU - Smerdon, Stephen J

PY - 2012/5

Y1 - 2012/5

N2 - Mdc1 is a large modular phosphoprotein scaffold that maintains signaling and repair complexes at double-stranded DNA break sites. Mdc1 is anchored to damaged chromatin through interaction of its C-terminal BRCT-repeat domain with the tail of γH2AX following DNA damage, but the role of the N-terminal forkhead-associated (FHA) domain remains unclear. We show that a major binding target of the Mdc1 FHA domain is a previously unidentified DNA damage and ATM-dependent phosphorylation site near the N-terminus of Mdc1 itself. Binding to this motif stabilizes a weak self-association of the FHA domain to form a tight dimer. 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 FHA domain-mediated interactions in human cells prior to and following DNA damage.

AB - Mdc1 is a large modular phosphoprotein scaffold that maintains signaling and repair complexes at double-stranded DNA break sites. Mdc1 is anchored to damaged chromatin through interaction of its C-terminal BRCT-repeat domain with the tail of γH2AX following DNA damage, but the role of the N-terminal forkhead-associated (FHA) domain remains unclear. We show that a major binding target of the Mdc1 FHA domain is a previously unidentified DNA damage and ATM-dependent phosphorylation site near the N-terminus of Mdc1 itself. Binding to this motif stabilizes a weak self-association of the FHA domain to form a tight dimer. 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 FHA domain-mediated interactions in human cells prior to and following DNA damage.

U2 - 10.1093/nar/gkr1300

DO - 10.1093/nar/gkr1300

M3 - Journal article

C2 - 22234878

SN - 0305-1048

VL - 40

SP - 4913

EP - 4928

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 9

ER -