# Processing and Repair of DNA Crosslinks

> **NIH NIH P01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $1,842,466

## Abstract

PROJECT SUMMARY
DNA crosslinks, including interstrand crosslinks (ICLs) and DNA-protein crosslinks (DPCs) are forms of DNA
damage that arise continuously in DNA from endogenous and natural sources. They must be removed in order
to allow accurate genome duplication and gene expression. Many chemotherapeutic agents induce ICLs
including nitrogen mustards and derivatives (melphalan, chlorambucil), psoralens, mitomycin C, platinum-
based compounds such as cisplatin, and nitrosoureas such as BCNU. Identification and future development of
biomarkers associated with ICL repair proficiency will facilitate precision medical treatment for individual
patients. Despite the importance of crosslinks in cancer etiology and treatment, mechanisms of DNA crosslink
repair are known only in outline, and many steps are simply assumed. An integrated, programmatic approach
involving four Research Projects and two service Cores will conduct experimental investigations under the
auspices of the Program and contribute, both individually and synergistically, to this theme. Each Overall
Goal/Specific Aim is independently engaged by each project using distinct and complementary approaches.
The Program Project is organized around three aims, representing goals of the project:
Aim 1: Determine how different pathways of crosslink repair are used or coordinated. The program will
investigate major gaps in knowledge about different crosslink repair pathways, including how nucleases or
complexes/components are recruited and used in different situations, variations of crosslink repair during the
cell cycle, action of crosslink repair at different configurations of model stalled replication forks, whether ICL
repair differs for different lesions, and the mechanism of error-free and mutagenic crosslink repair. Aim 2:
Understand functions of newly discovered and little-studied crosslink repair components. One block to
progress in understanding repair of ICLs is that there are a group of components that are known to be involved
in crosslink repair, but where mechanistic roles are unassigned or known only superficially. In this program the
investigators will cooperate to determine their functions. Major unknown components include SLX4IP (which
associates with SLX4); the HMGB1, HMGB2 and HMGB3 DNA binding proteins; the MSH2-MSH3 complex
(which binds DNA distortions); and UHRF1 (postulated as an alternative scaffold for delivery of nucleases).
Aim 3: Investigate the mechanisms of repair of DNA-protein crosslinks. There are likely to be several routes of
DPC repair and tolerance. Experiments will be undertaken to determine different modes of processing. Major
gaps in knowledge include the involvement of Fanconi anemia (FA) pathway proteins in repair and how
features of FA might be explained by defects in DPC repair. We will investigate involvement of replicative
bypass (translesion DNA synthesis) in tolerance of DNA-peptide crosslinks (modeling proteolytically processed
DPCs). We will also ...

## Key facts

- **NIH application ID:** 10129289
- **Project number:** 5P01CA193124-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** RICHARD D WOOD
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,842,466
- **Award type:** 5
- **Project period:** 2017-02-10 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129289

## Citation

> US National Institutes of Health, RePORTER application 10129289, Processing and Repair of DNA Crosslinks (5P01CA193124-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129289. Licensed CC0.

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