Related Experiment Video
Updated: Aug 14, 2025
Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
Published on: September 28, 2012
DNA repair protein FANCD2 has both ubiquitination-dependent and ubiquitination-independent functions during germ cell
Simin Zhao1, Chengzi Huang1, Yajuan Yang1
1Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China; Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China; Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, China; Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, China; Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China.
Abstract:
When DNA interstrand crosslink lesions occur, a core complex of Fanconi anemia proteins promotes the ubiquitination of FANCD2 and FANCI, which recruit downstream factors to repair the lesion. However, FANCD2 maintains genome stability not only through its ubiquitination-dependent but also its ubiquitination-independent functions in various DNA damage response pathways. Increasing evidence suggests that FANCD2 is essential for fertility, but its ubiquitination-dependent and ubiquitination-independent roles during germ cell development are not well characterized. In this study, we analyzed germ cell development in Fancd2 KO and ubiquitination-deficient mutant (Fancd2K559R/K559R) mice. We showed that in the embryonic stage, both the ubiquitination-dependent and ubiquitination-independent functions of FANCD2 were required for the expansion of primordial germ cells and establishment of the reproductive reserve by reducing transcription-replication conflicts and thus maintaining genome stability in primordial germ cells. Furthermore, we found that during meiosis in spermatogenesis, FANCD2 promoted chromosome synapsis and regulated crossover formation independently of its ubiquitination, but that both ubiquitinated and nonubiquitinated FANCD2 functioned in programmed double strand break repair. Finally, we revealed that on meiotic XY chromosomes, H3K4me2 accumulation required ubiquitination-independent functionality of FANCD2, while the regulation of H3K9me2 and H3K9me3 depended on FANCD2 ubiquitination. Taken together, our findings suggest that FANCD2 has distinct functions that are both dependent on and independent of its ubiquitination during germ cell development.
Insights
Fanconi anemia protein FANCD2 is crucial for fertility, with both its ubiquitination-dependent and independent functions supporting germ cell development and genome stability.
Area of Science:
- Genetics
- Molecular Biology
- Reproductive Biology
Background:
- Fanconi anemia protein FANCD2 plays a role in DNA repair and genome stability.
- FANCD2 has both ubiquitination-dependent and independent functions in DNA damage response.
- The specific roles of FANCD2 in germ cell development are not fully understood.
Purpose of the Study:
- To investigate the distinct roles of ubiquitination-dependent and independent FANCD2 functions in mouse germ cell development.
- To elucidate FANCD2's contribution to primordial germ cell expansion and meiotic processes.
Main Methods:
- Analysis of germ cell development in wild-type, Fancd2 knockout (KO), and ubiquitination-deficient mutant (Fancd2K559R/K559R) mice.
- Assessment of primordial germ cell proliferation, meiotic progression, and chromosomal events.
Main Results:
- Both ubiquitination-dependent and independent FANCD2 functions are essential for primordial germ cell expansion and genome stability by mitigating transcription-replication conflicts.
- FANCD2 independently regulates chromosome synapsis and crossover formation during meiosis.
- Both ubiquitinated and non-ubiquitinated FANCD2 are involved in programmed double-strand break repair.
- Ubiquitination-independent FANCD2 is required for H3K4me2 accumulation on meiotic XY chromosomes, while ubiquitination-dependent FANCD2 regulates H3K9me2 and H3K9me3.
Conclusions:
- FANCD2 exhibits distinct, essential functions in germ cell development that are both dependent on and independent of its ubiquitination.
- These findings highlight the complex regulatory roles of FANCD2 in ensuring fertility and maintaining genome integrity during gametogenesis.
Related Concept Videos
02:37DNA Damage can Stall the Cell Cycle
02:37Restarting Stalled Replication Forks
01:23Negative Regulator Molecules
02:04Fixing Double-strand Breaks
01:02Long-patch Base Excision Repair
01:38Nucleotide Excision Repair
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...