Molecular Cell
Volume 9, Issue 5, May 2002, Pages 1045-1054
Journal home page for Molecular Cell

Article
Structural and Functional Versatility of the FHA Domain in DNA-Damage Signaling by the Tumor Suppressor Kinase Chk2

https://doi.org/10.1016/S1097-2765(02)00527-0Get rights and content
Under an Elsevier user license
open archive

Abstract

The Chk2 Ser/Thr kinase plays crucial, evolutionarily conserved roles in cellular responses to DNA damage. Identification of two pro-oncogenic mutations within the Chk2 FHA domain has highlighted its importance for Chk2 function in checkpoint activation. The X-ray structure of the Chk2 FHA domain in complex with an in vitro selected phosphopeptide motif reveals the determinants of binding specificity and shows that both mutations are remote from the peptide binding site. We show that the Chk2 FHA domain mediates ATM-dependent Chk2 phosphorylation and targeting of Chk2 to in vivo binding partners such as BRCA1 through either or both of two structurally distinct mechanisms. Although phospho-dependent binding is important for Chk2 activity, previously uncharacterized phospho-independent FHA domain interactions appear to be the primary target of oncogenic lesions.

Cited by (0)

5

These authors contributed equally to this work.

6

Present address: Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada.

4

Correspondence: Stephen P. Jackson; e-mail: [email protected], and Stephen J. Smerdon, 44 208 959 3666 ext. 2512 (phone), 44 208 906 4477 (fax); e-mail: [email protected]