Slipped trinucleotide repeat repair by MutLalpha 1 Human mismatch repair protein hMutLalpha is required to repair short slipped-DNAs of trinucleotide repeats*
نویسندگان
چکیده
Background: Slipped-DNAs are mutagenic intermediates in disease-causing trinucleotide repeat instability; their processing is not well understood. Results: MutLα is required to repair single short slip-outs, and enhances repair of clustered slipouts. Conclusion: Aberrant mismatch repair attempts on clustered slip-outs may cause repeat instability. Significance: This work has determined one of the proteins involved in slipped-DNA repair, which is useful for understanding disease-causing repeat instability.
منابع مشابه
Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases.
The expansion of trinucleotide repeat sequences is associated with several neurodegenerative diseases. The mechanism of this expansion is unknown but may involve slipped-strand structures where adjacent rather than perfect complementary sequences of a trinucleotide repeat become paired. Here, we have studied the interaction of the human mismatch repair protein MSH2 with slipped-strand structure...
متن کاملIsolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSbeta, but clustered slip-outs are poorly repaired.
Expansions of CTG/CAG trinucleotide repeats, thought to involve slipped DNAs at the repeats, cause numerous diseases including myotonic dystrophy and Huntington's disease. By unknown mechanisms, further repeat expansions in transgenic mice carrying expanded CTG/CAG tracts require the mismatch repair (MMR) proteins MSH2 and MSH3, forming the MutSbeta complex. Using an in vitro repair assay, we i...
متن کاملInterconverting Conformations of Slipped-DNA Junctions Formed by Trinucleotide Repeats Affect Repair Outcome
Expansions of (CTG)·(CAG) repeated DNAs are the mutagenic cause of 14 neurological diseases, likely arising through the formation and processing of slipped-strand DNAs. These transient intermediates of repeat length mutations are formed by out-of-register mispairing of repeat units on complementary strands. The three-way slipped-DNA junction, at which the excess repeats slip out from the duplex...
متن کاملAbsence of MutSβ leads to the formation of slipped-DNA for CTG/CAG contractions at primate replication forks.
Typically disease-causing CAG/CTG repeats expand, but rare affected families can display high levels of contraction of the expanded repeat amongst offspring. Understanding instability is important since arresting expansions or enhancing contractions could be clinically beneficial. The MutSβ mismatch repair complex is required for CAG/CTG expansions in mice and patients. Oddly, by unknown mechan...
متن کاملLarge expansion of CTG•CAG repeats is exacerbated by MutSβ in human cells
Trinucleotide repeat expansion disorders (TRED) are caused by genomic expansions of trinucleotide repeats, such as CTG and CAG. These expanded repeats are unstable in germline and somatic cells, with potential consequences for disease severity. Previous studies have demonstrated the involvement of DNA repair proteins in repeat instability, although the key factors affecting large repeat expansi...
متن کامل