Abstract Details

Title Mechanisms of REV1-dependent Trinucleotide Repeat Instability

Topic Movement Disorders

Presentation(s) P12 - Poster Session 12 (11:45 AM-12:00 PM)

Poster/Presentation
Number 5-029

Objective

To explore the role of the translesion synthesis (TLS) polymerase REV1 in trinucleotide repeat (TNR) instability mechanisms.

Background The expansion and contraction of unstable trinucleotide repeat (TNR) regions in DNA is the physiologic basis behind numerous neurologic disorders. Drivers of TNR instability center around DNA replication and repair pathways, with recent studies investigating the role of TLS polymerases in TNR instability. These polymerases allow cells to replicate through existing DNA damage or repetitive DNA-induced secondary structures, generating new mutations or repeat length alterations, respectively. Recent evidence has also identified rereplication as a mechanism for TNR mutagenesis.

Design/Methods To investigate the relationship between REV1 and TNR instability, we used a human cell line model containing a quantitative GFP reporter of TNR instability. We employed REV1 inhibitors to limit REV1 and recovery from aphidicolin as a tool to create rereplication.

Results REV1 inhibition generally increased TNR instability, suggesting that REV1 is required to replicate through potential secondary structures, and its absence causes replication collapse and TNR instability. However, preliminary data suggests that REV1-inhibited cells exhibited reduced rereplication-dependent TNR instability, possibly due to REV1’s requirement to also replicate through rereplication-induced secondary structures.

Conclusions Our study unveils the pivotal role of REV1 in TNR instability, particularly in its capacity to replicate through secondary structures. Its absence leads to escalated TNR instability. Moreover, REV1’s participation in replication at these repeats is confirmed, as their collapse is more likely due to the lack of continued and necessary replication at repeat secondary structures. By inducing DNA rereplication, another catalyst of TNR instability, we demonstrate that REV1 is indispensable for this process. Understanding the role of TLS in TNR instability has profound implications for the field of genetics and molecular biology, offering insights into mechanisms behind TNR mutagenesis and its contribution to disease pathology.

Authors/Disclosures
Ava Siegel PRESENTER	Ms. Siegel has nothing to disclose.
Daniel A. Almstead	Mr. Almstead has nothing to disclose.
Lindsay P. Allen	Miss Allen has nothing to disclose.
Erica Lamkin, Student	Miss Lamkin has nothing to disclose.
Naveen Kothandaraman	Mr. Kothandaraman has nothing to disclose.
Kanayo E. Ikeh, PhD	Dr. Ikeh has nothing to disclose.
Hannah Koval	Miss Koval has nothing to disclose.
Andrew Crompton	Mr. Crompton has nothing to disclose.
Jessica Reich, Undergraduate	Miss Reich has nothing to disclose.
Roxana del Rio Guerra	Dr. del Rio Guerra has nothing to disclose.
Dmitry M. Korzhnev, PhD	The institution of Prof. Korzhnev has received research support from NIH.
Kyle Hadden, PhD	Dr. Hadden has nothing to disclose.
Jiyong Hong, PhD	Prof. Hong has nothing to disclose.
Pei Zhou, PhD	Dr. Zhou has nothing to disclose.
Nimrat Chatterjee, PhD	Dr. Chatterjee has received research support from Nih.

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