FANCD2–FANCI Complex Recognizes Double-Stranded to Single-Stranded DNA Junctions and Plays a Central Role in DNA Crosslink Repair and Replication Fork Protection

Основні поняття

The FANCD2-FANCI protein complex is a sliding clamp that binds and diffuses on double-stranded DNA, but stalls at single-stranded to double-stranded DNA junctions, which are generated at stalled replication forks. This allows the complex to recognize sites of DNA damage and coordinate DNA repair.

Анотація

The content describes the role of the FANCD2-FANCI (D2-I) protein complex in DNA repair and replication fork protection. Key points:

1. D2-I is central to the Fanconi anemia pathway, which repairs DNA crosslinks that block DNA replication.
2. D2-I also has a more general role in protecting stalled replication forks from degradation.
3. Using single-molecule imaging, the authors show that D2-I is a sliding clamp that binds and diffuses on double-stranded DNA.
4. Importantly, D2-I stalls when it encounters single-stranded to double-stranded DNA junctions, which are generated at stalled replication forks.
5. Cryo-EM structures reveal that stalled D2-I makes specific interactions with the single-stranded to double-stranded DNA junction, distinct from its sliding mode.
6. This allows D2-I to survey double-stranded DNA and recognize sites of DNA damage at stalled replication forks.
7. The authors propose a unified molecular mechanism that explains the roles of D2-I in both DNA repair and replication fork protection.

Статистика

DNA crosslinks block DNA replication.
D2-I coordinates DNA incisions around DNA lesions to initiate repair.
D2-I protects stalled replication forks from unscheduled degradation.
Single-stranded to double-stranded DNA junctions are generated when replication forks stall at DNA lesions.

Цитати

"D2–I surveys dsDNA and, when it reaches an ssDNA gap, it specifically clamps onto ss–dsDNA junctions."
"Because ss–dsDNA junctions are found at stalled replication forks, D2–I can identify sites of DNA damage."

Ключові висновки, отримані з

FANCD2–FANCI surveys DNA and recognizes double- to single-stranded junctions - Nature

by Pabl... о www.nature.com 07-31-2024

https://www.nature.com/articles/s41586-024-07770-w

Глибші Запити

How does the binding and sliding mechanism of D2-I on DNA enable it to coordinate different DNA repair pathways?

The binding and sliding mechanism of the FANCD2-FANCI (D2-I) complex on DNA plays a crucial role in coordinating various DNA repair pathways. By acting as a sliding clamp on double-stranded DNA, D2-I can efficiently survey the DNA for any abnormalities or lesions. This sliding mechanism allows D2-I to move along the DNA strands and recognize specific structures, such as single-stranded to double-stranded (ss-ds) DNA junctions that are indicative of stalled replication forks or DNA damage. When D2-I encounters these junctions, it stalls and makes specific interactions with the ss-dsDNA structure, initiating the repair process. This ability to recognize and bind to ss-dsDNA junctions enables D2-I to coordinate different DNA repair pathways by serving as a molecular sensor for DNA damage and replication stress.

What are the potential implications of disrupting the D2-I recognition of single-stranded to double-stranded DNA junctions for cancer treatment or other clinical applications?

Disrupting the recognition of single-stranded to double-stranded DNA junctions by the FANCD2-FANCI (D2-I) complex could have significant implications for cancer treatment and other clinical applications. Since D2-I plays a crucial role in DNA repair and replication fork protection, impairing its ability to identify ss-dsDNA junctions may lead to increased genomic instability and accumulation of DNA damage. In the context of cancer treatment, targeting the D2-I complex to disrupt its recognition of these junctions could potentially sensitize cancer cells to DNA-damaging agents, making them more susceptible to chemotherapy or other targeted therapies. Additionally, understanding the implications of disrupting D2-I recognition could provide insights into novel therapeutic strategies for cancer and other diseases characterized by DNA repair deficiencies.

What other cellular factors or signaling pathways might interact with the D2-I complex to regulate its function in DNA repair and replication fork protection?

Several cellular factors and signaling pathways are known to interact with the FANCD2-FANCI (D2-I) complex to regulate its function in DNA repair and replication fork protection. One key regulator is the FA core complex, which monoubiquitinates FANCD2, leading to its activation and recruitment to sites of DNA damage. Additionally, proteins involved in homologous recombination, such as BRCA1 and BRCA2, interact with D2-I to facilitate DNA repair processes. Signaling pathways like the ATR-Chk1 pathway, which is activated in response to replication stress, also crosstalk with D2-I to coordinate DNA repair activities. Furthermore, factors involved in chromatin remodeling and DNA damage response, such as histone modifications and DNA damage sensors, may influence the function of the D2-I complex in maintaining genome stability and protecting replication forks. Understanding the intricate network of interactions between D2-I and these cellular factors is essential for elucidating the comprehensive regulatory mechanisms governing DNA repair and replication fork protection.