Different sets of translesion synthesis DNA polymerases protect from genome instability induced by distinct...

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• DNA lesions impede replication forks, necessitating bypass mechanisms.
• Translesion synthesis (TLS) DNA polymerases (Pols) facilitate replication fork progression past DNA damage but can introduce mutations.
• Understanding the in vivo roles of specific TLS Pols in response to diverse genotoxins is crucial for comprehending DNA repair and mutagenesis.

Purpose of the Study:

• To investigate the in vivo roles of TLS Pols η, ι, κ, Rev1, and Rev3 in cellular responses to benzo[a]pyrene diolepoxide (BPDE) and 4-hydroxynonenal (4-HNE).
• To determine how these TLS polymerases influence cellular survival, replication fork progression, DNA damage responses (DDR), and micronuclei induction after genotoxic exposure.

Main Methods:

• Utilized mouse embryonic fibroblasts with targeted disruptions in TLS-associated Pols (η, ι, κ, Rev1) and Rev3.
• Exposed cells to BPDE and 4-HNE.
• Assessed cellular survival, replication fork progression, DDR activation, and micronuclei formation.

Main Results:

• Rev1, Rev3, and Polη play significant roles in TLS, preventing DDR and DNA breaks induced by both BPDE and 4-HNE.
• Polκ and the N-terminal BRCT domain of Rev1 are specifically involved in TLS of BPDE-induced DNA damage.
• Polι demonstrates a novel in vivo role in TLS of 4-HNE-induced DNA damage.

Conclusions:

• Different TLS polymerases are recruited to structurally distinct DNA lesions in vivo.
• This polymerase specialization helps suppress genomic instability and potentially cancer development.
• The findings contribute to understanding the molecular basis of genotoxicity for various DNA-damaging agents.