# RAD54L

## Overview
RAD54L is a gene located on human chromosome 1p32 that encodes the RAD54-like protein, a key player in the DNA repair process. The RAD54-like protein, distinct from the gene itself, is involved in homologous recombination, a critical mechanism for repairing DNA double-strand breaks and ensuring genomic stability. As a DNA-dependent ATPase, the protein facilitates the proper alignment and pairing of homologous DNA strands, working closely with Rad51 and other proteins to repair damaged DNA efficiently and maintain chromosomal integrity. This function is vital for preventing mutations that could lead to various diseases, including cancer. The protein's role extends beyond simple DNA repair, as it also influences chromosome condensation and segregation during cell division, further underscoring its importance in maintaining cellular and genomic health (Mun2020E2F1; Mason2015RAD54).

## Function
RAD54L, encoded by the RAD54L gene, is a crucial protein in human cells, primarily involved in the homologous recombination repair (HRR) of DNA double-strand breaks (DSBs). This protein functions as a double-stranded DNA-dependent ATPase and plays a significant role in maintaining genomic stability by facilitating accurate DNA repair, thus preventing mutations that could lead to diseases such as cancer (Mun2020E2F1). RAD54L acts as a cofactor for Rad51, a protein essential for the HRR pathway, helping to stabilize the Rad51-single-stranded DNA (ssDNA) filament necessary for the proper alignment and pairing of homologous DNA strands during repair. Additionally, RAD54L promotes DNA synthesis by facilitating the removal of Rad51 from the heteroduplex DNA, allowing the repair process to proceed (Mun2020E2F1).

Moreover, RAD54L, along with RAD54B, limits the accumulation of DNA-bound RAD51 complexes, which can occur even in the absence of DNA damage. Overexpression of RAD51 or depletion of RAD54L and RAD54B leads to significant genomic instability, characterized by defects in chromosome condensation and segregation during mitosis (Mason2015RAD54). This indicates that RAD54L is essential for proper chromosome condensation and segregation, thereby preventing genomic instability.

## Clinical Significance
RAD54L, a gene involved in DNA damage repair, has been implicated in various cancers due to mutations and alterations in its expression. In clear cell renal cell carcinoma (ccRCC), elevated RAD54L expression is associated with advanced tumor stages and poor prognosis, including worse overall survival and disease-specific survival (Wang2021Comprehensive). Similarly, in multiple myeloma (MM), RAD54L is significantly upregulated, and its overexpression correlates with disease progression. Silencing of RAD54L in MM cells has shown potential therapeutic benefits, such as reduced cell proliferation and increased apoptosis (Bong2022Gene).

Furthermore, a germline mutation in RAD54L has been linked to a hypermutated phenotype in colorectal cancer, suggesting a novel mechanism for cancer development through impaired DNA repair pathways (Zohud2020Germline). This mutation, combined with somatic mutations in other genes like POLE, contributes to high tumor mutation burdens and may influence cancer treatment strategies.

Overall, the clinical significance of RAD54L in cancer highlights its role not only in tumor progression but also as a potential target for therapeutic intervention, underscoring the importance of understanding gene function and regulation in the context of disease.

## Interactions
RAD54L, a DNA motor protein, engages in several critical physical interactions essential for its function in DNA repair processes, particularly during homologous recombination. It stabilizes RAD51 filaments during the pre-synaptic stage and assists in the removal of RAD51 from heteroduplex DNA to facilitate repair synthesis (Uhrig2023Disparate). Additionally, RAD54L promotes branch migration of Holliday junctions and the reversal and restoration of model replication forks. Its ATPase activity is crucial for converting the synaptic complex into a displacement-loop, essential for strand invasion during homologous recombination (Uhrig2023Disparate).

RAD54L is also involved in replication fork reversal pathways. In the FBH1 pathway, the branch migration activity of RAD54L is essential, whereas in the HLTF/SMARCAL1 pathway, this activity is dispensable, indicating different functional requirements in these pathways (Uhrig2023Disparate). Furthermore, RAD54L interacts with RAD51 and NUCKS1, as evidenced by its recruitment to stalled DNA replication forks upon treatment with hydroxyurea, a compound known to stall replication (Uhrig2023Disparate). These interactions highlight RAD54L's role in DNA repair and replication processes, underscoring its importance in maintaining genomic stability.


## References


[1. (Bong2022Gene) Ivyna Pau Ni Bong, Ching Ching Ng, Norodiyah Othman, and Ezalia Esa. Gene expression profiling and in vitro functional studies reveal rad54l as a potential therapeutic target in multiple myeloma. Genes & Genomics, 44(8):957–966, June 2022. URL: http://dx.doi.org/10.1007/s13258-022-01272-7, doi:10.1007/s13258-022-01272-7. (4 citations) 10.1007/s13258-022-01272-7](https://doi.org/10.1007/s13258-022-01272-7)

[2. (Mason2015RAD54) Jennifer M. Mason, Kritika Dusad, William Douglass Wright, Jennifer Grubb, Brian Budke, Wolf-Dietrich Heyer, Philip P. Connell, Ralph R. Weichselbaum, and Douglas K. Bishop. Rad54 family translocases counter genotoxic effects of rad51 in human tumor cells. Nucleic Acids Research, 43(6):3180–3196, March 2015. URL: http://dx.doi.org/10.1093/nar/gkv175, doi:10.1093/nar/gkv175. (211 citations) 10.1093/nar/gkv175](https://doi.org/10.1093/nar/gkv175)

[3. (Uhrig2023Disparate) Disparate requirements for RAD54L in replication fork reversal (2 citations) 10.1101/2023.07.26.550704](https://doi.org/10.1101/2023.07.26.550704)

[4. (Zohud2020Germline) Bisan Abdalfatah Zohud, Meiling Wang, and Xin Cai. Germline rad54l with somatic pole defect implicated in hypermutation phenotype: case report. BMC Gastroenterology, August 2020. URL: http://dx.doi.org/10.1186/s12876-020-01403-y, doi:10.1186/s12876-020-01403-y. (4 citations) 10.1186/s12876-020-01403-y](https://doi.org/10.1186/s12876-020-01403-y)

[5. (Wang2021Comprehensive) Comprehensive Analysis of DNA Damage Repair Genes and Identification of RAD54L as an Immunological and Prognostic Biomarker in Clear Cell Renal Cell Carcinoma and Other Cancers (0 citations) 10.21203/rs.3.rs-683866/v1](https://doi.org/10.21203/rs.3.rs-683866/v1)

[6. (Mun2020E2F1) Jeong-Yeon Mun, Seung-Woo Baek, Won Young Park, Won-Tae Kim, Seon-Kyu Kim, Yun-Gil Roh, Mi-So Jeong, Gi-Eun Yang, Jong-Ho Lee, Jin Woong Chung, Yung Hyun Choi, In-Sun Chu, and Sun-Hee Leem. E2f1 promotes progression of bladder cancer by modulating rad54l involved in homologous recombination repair. International Journal of Molecular Sciences, 21(23):9025, November 2020. URL: http://dx.doi.org/10.3390/ijms21239025, doi:10.3390/ijms21239025. (30 citations) 10.3390/ijms21239025](https://doi.org/10.3390/ijms21239025)