FANCD2, the Fanconi anemia group D2 protein, is a pivotal component of the Fanconi anemia (FA) signaling pathway, a key genomic maintenance pathway activated in response to replication stress [1,2,3,6,7,9]. It plays crucial roles in multiple cellular processes, especially in the cellular responses to DNA damage [3]. The central FA protein complex FANCI/FANCD2 (ID2) is activated by monoubiquitination and recruits DNA repair proteins for interstrand crosslink (ICL) repair and replication fork protection [2].

Under conditions of CYCLIN E-and drug-induced replication stress, phosphorylation of FANCD2 by CHK1 triggers its FBXL12-dependent proteasomal degradation, facilitating FANCD2 clearance at stalled replication forks, which promotes efficient DNA replication [1]. The splicing factor SRSF1 and FANCD2 interact physically and act together to suppress R-loop formation via mRNA export regulation [2]. PCNA K164 ubiquitination is required for FANCD2-dependent mitotic DNA synthesis (MiDAS), as FANCD2 mono-ubiquitination is reduced in PCNAK164R mutants, leading to reduced chromatin association and foci formation [4]. FANCD2-FANCI complex surveys double-stranded DNA, stalls at single-stranded-double-stranded (ss-ds) DNA junctions (generated when replication forks stall at DNA lesions), and specifically clamps onto ss-dsDNA junctions, thereby identifying sites of DNA damage [5]. PP2A dephosphorylates an inhibitory cluster in FANCD2, licensing its loading onto chromosomes in response to DNA damage, which is required for normal monoubiquitination of the FANCD2/FANCI complex and its chromosome loading [9]. In cancer research, FANCD2 is highly expressed in the malignant sonic hedgehog (SHH) medulloblastoma subtype, and its knockdown suppresses cell viability, mobility, and growth, and sensitizes cells to irradiation via ferroptosis [8]. In osteosarcoma, FANCD2 knockdown reduces cell viability, invasion, and migration, and induces ferroptosis by regulating the JAK2/STAT3 axis [10].

In summary, FANCD2 is essential for DNA damage response, replication fork protection, and regulation of multiple cellular processes. Studies using genetic models, although not specifically KO/CKO mouse models in the provided references, have revealed its role in various disease-related processes such as cancer. These findings contribute to understanding the biological functions of FANCD2 and provide potential therapeutic targets for cancers like SHH medulloblastoma and osteosarcoma.

References:

1. Brunner, Andrä, Li, Qiuzhen, Fisicaro, Samuele, Orre, Lukas M, Sangfelt, Olle. 2023. FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress. In Molecular cell, 83, 3720-3739.e8. doi:10.1016/j.molcel.2023.07.026. https://pubmed.ncbi.nlm.nih.gov/37591242/

2. Olazabal-Herrero, Anne, He, Boxue, Kwon, Youngho, Sung, Patrick, Kupfer, Gary M. 2024. The FANCI/FANCD2 complex links DNA damage response to R-loop regulation through SRSF1-mediated mRNA export. In Cell reports, 43, 113610. doi:10.1016/j.celrep.2023.113610. https://pubmed.ncbi.nlm.nih.gov/38165804/

3. Nepal, Manoj, Che, Raymond, Ma, Chi, Zhang, Jun, Fei, Peiwen. 2017. FANCD2 and DNA Damage. In International journal of molecular sciences, 18, . doi:10.3390/ijms18081804. https://pubmed.ncbi.nlm.nih.gov/28825622/

4. Leung, Wendy, Baxley, Ryan M, Traband, Emma, Shima, Naoko, Bielinsky, Anja-Katrin. 2023. FANCD2-dependent mitotic DNA synthesis relies on PCNA K164 ubiquitination. In Cell reports, 42, 113523. doi:10.1016/j.celrep.2023.113523. https://pubmed.ncbi.nlm.nih.gov/38060446/

5. Alcón, Pablo, Kaczmarczyk, Artur P, Ray, Korak Kumar, Rueda, David S, Passmore, Lori A. 2024. FANCD2-FANCI surveys DNA and recognizes double- to single-stranded junctions. In Nature, 632, 1165-1173. doi:10.1038/s41586-024-07770-w. https://pubmed.ncbi.nlm.nih.gov/39085614/

6. Li, Landing, Tan, Winnie, Deans, Andrew J. . Structural insight into FANCI-FANCD2 monoubiquitination. In Essays in biochemistry, 64, 807-817. doi:10.1042/EBC20200001. https://pubmed.ncbi.nlm.nih.gov/32725171/

7. Lemonidis, Kimon, Arkinson, Connor, Rennie, Martin L, Walden, Helen. 2021. Mechanism, specificity, and function of FANCD2-FANCI ubiquitination and deubiquitination. In The FEBS journal, 289, 4811-4829. doi:10.1111/febs.16077. https://pubmed.ncbi.nlm.nih.gov/34137174/

8. Zhou, Hong, Wang, Yan-Xia, Wu, Min, Wang, Yan, Bian, Xiu-Wu. 2024. FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis. In The Journal of pathology, 262, 427-440. doi:10.1002/path.6245. https://pubmed.ncbi.nlm.nih.gov/38229567/

9. Yang, Di, Bai, Fengxiang, Lopez Martinez, David, Cao, Lily Jiaqi, Cohn, Martin A. 2024. PP2A licenses the FANCD2/FANCI complex for chromosome loading. In Cell reports, 43, 114971. doi:10.1016/j.celrep.2024.114971. https://pubmed.ncbi.nlm.nih.gov/39535917/

10. Li, Xujun, Liu, Jiangyi. 2023. FANCD2 inhibits ferroptosis by regulating the JAK2/STAT3 pathway in osteosarcoma. In BMC cancer, 23, 179. doi:10.1186/s12885-023-10626-7. https://pubmed.ncbi.nlm.nih.gov/36814203/