Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Structures, Recruitment and Regulation of Key Components in DNA Damage Response

Funder Wellcome Charity-funded
Recipient organisation Imperial College London
Funding £2.0M
Period Jan 2019 — Jan 2024

In plain English

AI plain-English summary

Every human cell repairs thousands of DNA breaks each day, but when a double-strand break—the most dangerous type—goes unfixed, it can trigger cancer or accelerate aging. This project investigates the molecular machinery that cells use to perform that repair faithfully, focusing on a set of key proteins: the signalling kinases ATR and ATM, the chromatin remodeler INO80, and the tumour suppressors BRCA2, PALB2, and BRCA1. The researchers have already made major advances in understanding these proteins’ structures and core actions under a previous Wellcome Trust award. Now they want to learn how these components are recruited to damage sites and how their activity is regulated. This is fundamental science—there is no immediate clinical application. But the knowledge could eventually explain why certain mutations in BRCA1 or BRCA2 lead to breast and ovarian cancers, and it may suggest new targets for drugs that make cancer cells more vulnerable to DNA-damaging treatments. Similar fundamental work on DNA repair pathways has already underpinned the development of PARP inhibitors, a class of cancer drugs now in routine use.

View original technical description
Genome stability and integrity are extremely important for proper cellular functions. However, each cell suffers from tens of thousands of DNA damage daily. Cells have thus evolved a myriad of ways to deal with these damages. A double-strand break (DSB) is the most severe form of damage and cells have developed multiple pathways to ensure efficient repairs are carried out. Homologous recombination is a faithful repair process and a large number of proteins are involved in this pathway. We aim to characterize some of the key proteins in homologous recombination including the master signaling kinases ATR/ATM (Mec1/Tel1 in yeast), the chromatin remodeler INO80 and the tumour suppressors BRCA2, PALB2 and BRCA1. We have obtained significant breakthrough in some of the areas in the last five years funded by a Wellcome Trust Investigator award. In this current proposal, we will continue to investigate their structures and core mechanism of actions. More importantly, we now want to investigate how these key players are recruited and how they are regulated. The knowledge obtained will help us understand the causes of cancer and aging and can also provide new avenues for therapeutic development.

View the original record at the funder ↗

Researchers

Xiaodong Zhang (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Structures and mechanisms of key components in the DNA damage response.
Understanding the molecular basis of checkpoint response during DNA double-strand break repair
Structural Biology of DNA Damage Response and Repair Mechanisms
Structural Biology of Proteins and Complexes Involved in DNA Repair, Transcription Regulation and Signal Transduction
The structure and mechanism of proteins involved in double-strand DNA break repair

Original classification

Investigator Award in Science

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.