Eukaryotic stress-induced mutagenesis is limited by a local control of translesion synthesis

Area of Science:

• Molecular Biology
• Genetics
• Cellular Biology

Background:

• The DNA damage response (DDR) is crucial for maintaining genomic stability by detecting and repairing DNA damage.
• Translesion Synthesis (TLS) is an error-prone DNA damage tolerance pathway regulated by PCNA ubiquitination.
• The precise control mechanism of TLS, whether local or global, remained unclear.

Purpose of the Study:

• To investigate the local versus global control of Translesion Synthesis (TLS).
• To determine the role of PCNA ubiquitination in TLS regulation at individual DNA lesions.
• To compare the eukaryotic DDR's effect on TLS with the bacterial SOS response.

Main Methods:

• Utilized a novel method to track the bypass of single DNA lesions within the yeast genome.
• Analyzed PCNA ubiquitination in response to individual DNA lesions.
• Assessed the impact of genotoxic stress-induced DDR activation on TLS efficiency.

Main Results:

• TLS is regulated locally at each DNA lesion through PCNA ubiquitination.
• A single DNA lesion is sufficient to trigger PCNA ubiquitination.
• PCNA ubiquitination is essential for TLS to occur.
• Eukaryotic DDR activation does not enhance TLS at individual lesions.

Conclusions:

• TLS is under strict local control at the DNA lesion site, mediated by PCNA ubiquitination.
• The eukaryotic DNA damage response does not promote TLS or mutagenesis, contrasting with the bacterial SOS response.