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

Stephanie Jungmichel; Julie A Clapperton; Lloyd Janette; Flurina J Hari; Christoph Spycher; Lucijana Pavic; Jiejin Li; Lesley F Haire; Mario Bonalli; Dorthe Helena Larsen; Claudia Lukas; Jiri Lukas; Derek  MacMillan; Michael Lund Nielsen; Manuel Stucki; Stephen J Smerdon

doi:10.1093/nar/gkr1300

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

Stephanie Jungmichel, Julie A Clapperton, Lloyd Janette, Flurina J Hari, Christoph Spycher, Lucijana Pavic, Jiejin Li, Lesley F Haire, Mario Bonalli, Dorthe Helena Larsen, Claudia Lukas, Jiri Lukas, Derek MacMillan, Michael Lund Nielsen, Manuel Stucki, Stephen J Smerdon

Novo Nordisk Foundation Center for Protein Research

32 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Nucleic Acids Research
Volume	40
Issue number	9
Pages (from-to)	4913-4928
Number of pages	16
ISSN	0305-1048
DOIs	https://doi.org/10.1093/nar/gkr1300
Publication status	Published - May 2012

Access to Document

10.1093/nar/gkr1300

Cite this

Jungmichel, S., Clapperton, J. A., Janette, L., Hari, F. J., Spycher, C., Pavic, L., Li, J., Haire, L. F., Bonalli, M., Larsen, D. H., Lukas, C., Lukas, J., MacMillan, D., Nielsen, M. L., Stucki, M., & Smerdon, S. J. (2012). The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator. Nucleic Acids Research, 40(9), 4913-4928. https://doi.org/10.1093/nar/gkr1300

Jungmichel, S, Clapperton, JA, Janette, L, Hari, FJ, Spycher, C, Pavic, L, Li, J, Haire, LF, Bonalli, M, Larsen, DH, Lukas, C, Lukas, J, MacMillan, D, Nielsen, ML, Stucki, M & Smerdon, SJ 2012, 'The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator.', Nucleic Acids Research, vol. 40, no. 9, pp. 4913-4928. https://doi.org/10.1093/nar/gkr1300

@article{ba07fd7d1e694e2bbc8622d592b6431a,

title = "The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator.",

abstract = "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.",

author = "Stephanie Jungmichel and Clapperton, {Julie A} and Lloyd Janette and Hari, {Flurina J} and Christoph Spycher and Lucijana Pavic and Jiejin Li and Haire, {Lesley F} and Mario Bonalli and Larsen, {Dorthe Helena} and Claudia Lukas and Jiri Lukas and Derek MacMillan and Nielsen, {Michael Lund} and Manuel Stucki and Smerdon, {Stephen J}",

year = "2012",

month = may,

doi = "10.1093/nar/gkr1300",

language = "English",

volume = "40",

pages = "4913--4928",

journal = "Nucleic Acids Research",

issn = "0305-1048",

publisher = "Oxford University Press",

number = "9",

}

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 -

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

Abstract

Access to Document

Fingerprint

Cite this