DNA damage promotes hematopoietic stem cell (HSC) aging, but the underlying molecular mechanisms are not fully understood.
On April 17, 2024, the team led by Wang Jianwei from the Chinese Academy of Medical Sciences Blood Disease Hospital (Institute of Hematology, Chinese Academy of Medical Sciences), with Dr. He Hanqing as the first author, published an online research paper titled “Aging-induced MCPH1 translocation activates necroptosis and impairs hematopoietic stem cell function” in Nature Aging . This study demonstrates that aging-induced MCPH1 translocation activates necroptosis and impairs hematopoietic stem cell function.
Hematopoietic stem cells are responsible for producing all blood cells throughout a person’s life. As hematopoietic stem cells age, their function deteriorates, their regenerative capacity declines, and they tend to differentiate towards myeloid lineage, which is a risk factor for myeloid malignancies. While the role of accumulated DNA damage in driving HSC aging is widely recognized, the complete molecular cascade leading to HSC degeneration due to DNA damage remains to be fully elucidated. MCPH1, also known as BRIT1 (BRCT-hTERT expression repressor), is identified as the initial gene driving primary autosomal recessive microcephaly. Its functional roles include various cellular functions, including participation in DNA damage response, chromosome condensation regulation, cell cycle progression, centrosome activity, and metabolism.
MCPH1 plays a critical role in recruiting DNA damage sensors and mediators (such as CHK1, 53BP1, MDC1, NBS1, ATM, and RPA) to repair DNA double-strand breaks. Structurally, MCPH1 contains three BRCT (BRCA C-terminal) domains, where the N-terminal BRCT determines MCPH1-related phenotypes, and the C-terminal BRCT regulates self-oligomerization, playing an important role in ionizing radiation induced lesion formation.Additionally, MCPH1 participates in chromatin remodeling during DNA damage through interaction with the SWI-SNF complex and serves as a key regulatory factor at the cell cycle checkpoint, particularly during S phase and G2/M phase.
Mcph1 dysfunction severely impairs the regenerative capacity of hematopoietic stem cells (Credit: Nature Aging)
This study discovered the heterogeneous functional roles of microcephalin (MCPH1) in the nucleus and cytoplasm of mouse hematopoietic stem cells. In the nucleus, MCPH1 maintains genomic stability, while in the cytoplasm, it prevents necroptosis by binding to p-RIPK3. Aging triggers the translocation of MCPH1 from the cytoplasm to the nucleus, reducing its cytoplasmic retention, leading to the activation of necroptosis and deterioration of HSC function.
Mechanistically, the study found that in the NLS motif of MCPH1, KAT7-mediated lysine acetylation promotes its nuclear translocation in response to DNA damage. Targeted mutations of these lysines inhibit MCPH1 translocation, resulting in necroptosis. Dysfunction of necroptosis signaling, in turn, improves the function of aging HSCs. In summary, the findings suggest that DNA damage-induced MCPH1 redistribution promotes HSC aging and may have broader implications for aging and age-related diseases.
https://www.nature.com/articles/s43587-024-00609-z
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