Structure of the human MutSalpha DNA lesion recognition complex.

Published

Journal Article

Mismatch repair (MMR) ensures the fidelity of DNA replication, initiates the cellular response to certain classes of DNA damage, and has been implicated in the generation of immune diversity. Each of these functions depends on MutSalpha (MSH2*MSH6 heterodimer). Inactivation of this protein complex is responsible for tumor development in about half of known hereditary nonpolyposis colorectal cancer kindreds and also occurs in sporadic tumors in a variety of tissues. Here, we describe a series of crystal structures of human MutSalpha bound to different DNA substrates, each known to elicit one of the diverse biological responses of the MMR pathway. All lesions are recognized in a similar manner, indicating that diversity of MutSalpha-dependent responses to DNA lesions is generated in events downstream of this lesion recognition step. This study also allows rigorous mapping of cancer-causing mutations and furthermore suggests structural pathways for allosteric communication between different regions within the heterodimer.

Full Text

Duke Authors

Cited Authors

  • Warren, JJ; Pohlhaus, TJ; Changela, A; Iyer, RR; Modrich, PL; Beese, LS

Published Date

  • May 2007

Published In

Volume / Issue

  • 26 / 4

Start / End Page

  • 579 - 592

PubMed ID

  • 17531815

Pubmed Central ID

  • 17531815

Electronic International Standard Serial Number (EISSN)

  • 1097-4164

International Standard Serial Number (ISSN)

  • 1097-2765

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2007.04.018

Language

  • eng