What is it about?

This study has uncovered a novel line of communication between the nucleus and the endoplasmic reticulum that is pivotal for cellular responses to alkylating agents, a class of drugs commonly used in cancer chemotherapy and also found in environmental pollutants, such as cigarette smoke and fuel combustion products. This line of communication depends on a repair enzyme called AAG. AAG plays a critical role in DNA repair, snipping out DNA bases damaged by alkylating agents. To respond to alkylating agents, however, cells used AAG not only to repair DNA damage, but also to trigger endoplasmic reticulum stress responses.

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Why is it important?

We defined that the enzymatic activity of AAG, of snipping out bases, is not required for the activation of this ER stress response. Even AAG enzymes that were catalytically dead, and could not do DNA repair, i.e. could not snip the damaged bases, still could activate the ER response. We also found that AAG communicates with XBP1, a transcription factor that is activated during ER stress. Cells lacking AAG did not activate XBP1, while cells expressing AAG, either normal or catalytically dead, can activate XBP1. This study thus describes a non-canonical function for the DNA repair protein AAG in regulating ER stress response pathways.

Perspectives

This work is the result of a collaboration between several different institutions, in the UK, US, Brazil and Canada. Working with this diverse and multinational team was not without its challenges, but we all found it extremely enriching and rewarding. Our hope is that this work can inspire further collaborations and discoveries in what we think is a fascinating area of research.

Dr. Lisiane Borges Meira
University of Surrey

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This page is a summary of: A DNA repair-independent role for alkyladenine DNA glycosylase in alkylation-induced unfolded protein response, Proceedings of the National Academy of Sciences, February 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2111404119.
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