Excision of translesion synthesis errors orchestrates responses to helix-distorting DNA lesions

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• DNA mismatch repair (MMR) proteins are known for correcting nucleotide mismatches.
• MMR proteins also play roles in cellular responses to DNA damage, including mutagenic, cell cycle, and apoptotic pathways.
• The precise mechanisms underlying these responses to aberrant DNA lesions are not fully understood.

Purpose of the Study:

• To investigate the mechanistic basis of MMR-mediated cellular responses to DNA damage.
• To elucidate the role of MMR in conjunction with nucleotide excision repair (NER) and translesion synthesis (TLS) pathways.
• To understand how MMR proteins handle DNA photolesions induced by ultraviolet (UV) light.

Main Methods:

• Exposing cell lines with genetic defects in NER, TLS, and MMR to low-dose UV light during the S phase.
• Analyzing the roles of specific MMR proteins, such as the Msh2/Msh6 heterodimer.
• Investigating the induction of DNA checkpoints and double-strand breaks.

Main Results:

• The MMR heterodimer Msh2/Msh6 excises incorrect nucleotides incorporated by TLS opposite DNA photolesions.
• This excision creates single-stranded DNA patches that activate canonical Rpa-Atr-Chk1 checkpoints.
• These DNA lesions subsequently lead to double-strand breaks and apoptosis in the next cell cycle.

Conclusions:

• A novel MMR-related DNA excision repair pathway acts postreplicatively to control TLS.
• This pathway initiates cellular responses to genotoxic lesions, including checkpoints and apoptosis.
• These findings offer a potential explanation for the predisposition to colorectal cancer in Lynch syndrome patients with inherited MMR gene defects.