# Critical role of alpha spectrin in DNA repair: the importance of μ-calpain and Fanconi anemia proteins

## TL;DR

This paper shows that alpha spectrin is crucial for DNA repair, and its breakdown by μ-calpain causes defects in Fanconi anemia.

## Contribution

The study reveals a novel mechanistic link between μ-calpain activity, αSpII stability, and DNA repair in Fanconi anemia.

## Key findings

- Loss of αSpII due to μ-calpain cleavage impairs DNA interstrand crosslink repair in Fanconi anemia cells.
- Knockdown of μ-calpain restores αSpII levels and DNA repair capabilities in FA cells.
- FA proteins are proposed to maintain αSpII stability and prevent its cleavage by μ-calpain.

## Abstract

Nonerythroid spectrins are proteins important in maintaining the structural integrity and flexibility of the cell and nuclear membranes and are essential for a number of functionally important cellular processes. One of these proteins, nonerythroid α spectrin (αSpII), plays a critical role in DNA repair, specifically repair of DNA interstrand crosslinks (ICLs), where it acts as a scaffold, recruiting repair proteins to sites of damage. Loss or breakdown of αSpII is an important factor in a number of disorders. One of these is Fanconi anemia (FA), a genetic disorder characterized by bone marrow failure, chromosome instability, cancer predisposition, congenital abnormalities and a defect in DNA ICL repair. Significantly, breakdown of αSpII occurs in cells from a number of FA complementation groups, due to excessive cleavage by the protease, μ-calpain, leading to defective repair of DNA ICLs in telomeric and non-telomeric DNA. Knockdown of μ-calpain in FA cells by μ-calpain siRNA results in restoration of αSpII levels to normal and repair of DNA ICLs in telomeric and non-telomeric DNA, demonstrating the importance of αSpII stability in the repair process. It is hypothesized that there is a mechanistic link between excessive cleavage of αSpII by μ-calpain and defective DNA ICL repair in FA and that FA proteins, which are deficient in FA, play a key role in maintaining the stability of αSpII and preventing its cleavage by μ-calpain. All of these events are proposed to be important key factors involved in the pathophysiology of FA and suggest new avenues for potential therapeutic intervention.