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RAD51 and PALB2 in precision oncology: Clinical implications for HRD associated breast and ovarian cancers (Review)

  • Authors:
    • Mohd Adnan Kausar
    • Khalid Farhan Alshammari
    • Fahaad Alenazi
    • Sadaf Anwar
    • Amany Mohammed Khalifa
    • Tarig Ginawi
    • Abdulaziz Asiri
    • Mohammad Zeeshan Najm
    • Syed Arman Rabbani
    • Mohamed El‑Tanani
    • Saumyatika Gantayat
  • View Affiliations / Copyright

    Affiliations: Department of Biochemistry, College of Medicine, University of Ha'il, Hail 2440, Saudi Arabia, Department of Internal Medicine, College of Medicine, University of Ha'il, Hail 2440, Saudi Arabia, Department of Pharmacology, College of Medicine, University of Ha'il, Hail 2440, Saudi Arabia, Department of Pathology, College of Medicine, University of Ha'il, Hail 2440, Saudi Arabia, Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 67714, Saudi Arabia, School of Biosciences, Apeejay Stya University, Gurugram, Haryana 122103, India, Department of Clinical Pharmacy and Pharmacology, RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates, RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
    Copyright: © Kausar et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 65
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    Published online on: July 3, 2025
       https://doi.org/10.3892/ijo.2025.5771
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Abstract

Maintaining genomic stability is essential for reducing the risk of carcinogenesis. Homologous recombination (HR) is a high‑fidelity DNA repair mechanism that addresses double‑strand breaks and interstrand crosslinks. The present review examined two key components of HR: RAD51, the eukaryotic recombinase and PALB2, a scaffolding protein. Their structural and functional roles are explored in the context of breast and ovarian cancer. RAD51 facilitates homology search and strand invasion, while PALB2 links BRCA1 and BRCA2, stabilizing RAD51 filaments. Mutations in these genes compromise HR, increasing susceptibility to various cancers and impacting treatment efficacy by impairing DNA repair. The present review discussed the clinical implications of RAD51 and PALB2 mutations, focusing on risk stratification, PARP inhibitor efficacy and emerging therapies. Additionally, it highlighted the potential of RAD51 and PALB2 as biomarkers and therapeutic targets, contributing to advances in personalized cancer management.
View Figures

Figure 1

Schematic representation of the
current review underscoring the clinical implication of
RAD51 and PALB2 in breast and ovarian carcinomas.

Figure 2

Domain organization of RAD51.
NTD and Core domain (DOG 1.0 illustrator).

Figure 3

Domain organization of PALB2.
NTD, Middle region and C-terminal region (DOG 1.0 illustrator).

Figure 4

Initiation of HRR and the interaction
mechanisms of RAD51, PALB2 and BRCA2. (A) The
mechanism of HR initiation and the role of other proteins in
facilitating this process. The repair of a double-stranded DNA
break requires several essential proteins and complexes. The MRN
complex first identifies the DSB and attaches to the location.
Subsequently, it recruits ATM kinase, which phosphorylates
BRCA1, facilitating its recruitment to the site of injury.
During the S phase, RPA protein complex binds to the exposed
single-stranded DNA created by end resection, allowing the
BRCA1-PALB2-BRCA2 complex to load RAD51 onto the DNA,
enabling HRR, where RAD51 actively searches for a homologous
DNA strand to repair the break, with RPA being displaced once
RAD51 is bound. (B) Another possible pathway is via the NHEJ
pathway. In the G1 phase of the cell cycle, NHEJ is
primarily triggered if there is a presence of protein 53BP1 which
plays a crucial role in the process, and KU70/KU80 heterodimers
binds to the broken ends, facilitating the recruitment of the
DNA-PKcs, XRCC4 and LIG4 to finally join the DNA ends back
together. (C) The effect of presence and absence of BRCA1 on
RAD51 and PALB2. In the BRCA +/+ state, all
the interactions and recruitments among the genes and proteins in
normal cell is stable. PALB2 recruit BRCA1 by direct
interaction and it also interacts with MRG15, which is a
chromodomain containing proteins that bind histone H3K36me3.
Sufficient amount of RAD51 is also loaded onto the DNA and
RNF168 acts as stabilizing factor for these interactions. Whereas
in the BRCA -/- state, the Shieldin complex is active which
inhibits the binding of BRCA2-PALB2-RAD51 complex
effectively preventing the RAD51 recruitment to the damage
site leading to impaired HRR. HRR, homologous recombination repair;
HR, homologous recombination; MRN, Mre11-Rad50-Nbs1; DSB,
double-strand break; ATM Ataxia Telangiectasia Mutated; RPA,
replication protein A; NHEJ, non-homologous end joining; DNA-PKcs,
DNA-dependent protein kinase catalytic subunit; LIG4, Ligase IV;
H3K36me3, H3 trimethylated at lysine 36.

Figure 5

Synthetic lethality exhibits PARPi.
PARP, poly-(ADP-ribose) polymerase; PARPi, PARP inhibitors; HR,
homologous recombination; ss, single-stranded.

Figure 6

Clinical trials of key PARP
inhibitors in breast, ovarian, and prostate cancers. PARP,
poly-(ADP-ribose) polymerase; PARPi, PARP inhibitors.
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Copy and paste a formatted citation
Spandidos Publications style
Kausar MA, Alshammari KF, Alenazi F, Anwar S, Khalifa AM, Ginawi T, Asiri A, Najm MZ, Rabbani SA, El‑Tanani M, El‑Tanani M, et al: <em>RAD51</em> and <em>PALB2</em> in precision oncology: Clinical implications for HRD associated breast and ovarian cancers (Review). Int J Oncol 67: 65, 2025.
APA
Kausar, M.A., Alshammari, K.F., Alenazi, F., Anwar, S., Khalifa, A.M., Ginawi, T. ... Gantayat, S. (2025). <em>RAD51</em> and <em>PALB2</em> in precision oncology: Clinical implications for HRD associated breast and ovarian cancers (Review). International Journal of Oncology, 67, 65. https://doi.org/10.3892/ijo.2025.5771
MLA
Kausar, M. A., Alshammari, K. F., Alenazi, F., Anwar, S., Khalifa, A. M., Ginawi, T., Asiri, A., Najm, M. Z., Rabbani, S. A., El‑Tanani, M., Gantayat, S."<em>RAD51</em> and <em>PALB2</em> in precision oncology: Clinical implications for HRD associated breast and ovarian cancers (Review)". International Journal of Oncology 67.2 (2025): 65.
Chicago
Kausar, M. A., Alshammari, K. F., Alenazi, F., Anwar, S., Khalifa, A. M., Ginawi, T., Asiri, A., Najm, M. Z., Rabbani, S. A., El‑Tanani, M., Gantayat, S."<em>RAD51</em> and <em>PALB2</em> in precision oncology: Clinical implications for HRD associated breast and ovarian cancers (Review)". International Journal of Oncology 67, no. 2 (2025): 65. https://doi.org/10.3892/ijo.2025.5771
Copy and paste a formatted citation
x
Spandidos Publications style
Kausar MA, Alshammari KF, Alenazi F, Anwar S, Khalifa AM, Ginawi T, Asiri A, Najm MZ, Rabbani SA, El‑Tanani M, El‑Tanani M, et al: <em>RAD51</em> and <em>PALB2</em> in precision oncology: Clinical implications for HRD associated breast and ovarian cancers (Review). Int J Oncol 67: 65, 2025.
APA
Kausar, M.A., Alshammari, K.F., Alenazi, F., Anwar, S., Khalifa, A.M., Ginawi, T. ... Gantayat, S. (2025). <em>RAD51</em> and <em>PALB2</em> in precision oncology: Clinical implications for HRD associated breast and ovarian cancers (Review). International Journal of Oncology, 67, 65. https://doi.org/10.3892/ijo.2025.5771
MLA
Kausar, M. A., Alshammari, K. F., Alenazi, F., Anwar, S., Khalifa, A. M., Ginawi, T., Asiri, A., Najm, M. Z., Rabbani, S. A., El‑Tanani, M., Gantayat, S."<em>RAD51</em> and <em>PALB2</em> in precision oncology: Clinical implications for HRD associated breast and ovarian cancers (Review)". International Journal of Oncology 67.2 (2025): 65.
Chicago
Kausar, M. A., Alshammari, K. F., Alenazi, F., Anwar, S., Khalifa, A. M., Ginawi, T., Asiri, A., Najm, M. Z., Rabbani, S. A., El‑Tanani, M., Gantayat, S."<em>RAD51</em> and <em>PALB2</em> in precision oncology: Clinical implications for HRD associated breast and ovarian cancers (Review)". International Journal of Oncology 67, no. 2 (2025): 65. https://doi.org/10.3892/ijo.2025.5771
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