存储着我们的遗传信息的DNA在我们的一生当中持续地遭受损伤。如果不能正确地修复,那么DNA损伤会导致细胞死亡。而这又能够导致组织衰竭和衰老或者诱导突变产生从而使得细胞不受控制地增殖而导致癌症。基因Brca1在调节DNA修复中发挥着作用。Brca1发生突变能够导致人们患上家族性和散发性乳腺癌和卵巢癌。
在一项新的研究中,研究人员证实Brca1在维持毛囊干细胞(follicle stem cell)中发挥着关键性的作用。相关研究于2012年12月27日在线发表在Genes and Development期刊上,论文标题为"BRCA1 deficiency in skin epidermis leads to selective loss of hair follicle stem cells and their progeny"。
研究人员证实一旦剔除表皮中与乳腺癌相关联的基因Brca1,毛囊干细胞呈现出高水平的DNA损伤和细胞死亡。这种细胞损伤和死亡诱导毛囊干细胞过度增殖,并且最终让它们耗竭,从而导致毛囊退化。相反,位于表皮中的形成皮肤屏障和皮脂腺(sebaceous gland)的其他类型干细胞被维持,在基因BRCA1不存在时,它们也能够继续发挥正常的功能。这种差异体现出不同类型的成体干细胞对BRCA1有不同的需求。论文第一作者Peggy Sotiropoulou评论道,"我们非常吃惊地观察到位于相同组织的不同类型细胞对剔除相同的在DNA修复中发挥着至关重要作用的基因所作出的如此非常不同的反应。"
这项对于人们理解不同类型成体干细胞中的DNA修复机制以及它们的不同激活阶段是非常重要的。如果体内其他的干细胞也需要BRCA1 才能存活的话,那么这种研究结果可能潜在地解释为何女性的Brac1突变偏好地只导致乳腺癌和卵巢癌产生。(生物谷Bioon.com)
doi: 10.1101/gad.206573.112
PMC:
PMID:
BRCA1 deficiency in skin epidermis leads to selective loss of hair follicle stem cells and their progeny
Panagiota A. Sotiropoulou1,5,6, Andrea E. Karambelas1,5, Maud Debaugnies1, Aurelie Candi1, Peter Bouwman2, Virginie Moers1, Tatiana Revenco1, Ana Sofia Rocha1, Kiyotoshi Sekiguchi3, Jos Jonkers2 and Cedric Blanpain1,4,6
The accurate maintenance of genomic integrity is essential for tissue homeostasis. Deregulation of this process leads to cancer and aging. BRCA1 is a critical mediator of this process. Here, we performed conditional deletion of Brca1 during epidermal development and found that BRCA1 is specifically required for hair follicle (HF) formation and for development of adult HF stem cells (SCs). Mice deficient for Brca1 in the epidermis are hairless and display a reduced number of HFs that degenerate progressively. Surprisingly, the interfollicular epidermis and the sebaceous glands remain unaffected by Brca1 deletion. Interestingly, HF matrix transient amplifying progenitors present increased DNA damage, p53 stabilization, and caspase-dependent apoptosis compared with the interfollicular and sebaceous progenitors, leading to hyperproliferation, apoptosis, and subsequent depletion of the prospective adult HF SCs. Concomitant deletion of p53 and Brca1 rescues the defect of HF morphogenesis and loss of HF SCs. During adult homeostasis, BRCA1 is dispensable for quiescent bulge SCs, but upon their activation during HF regeneration, Brca1 deletion causes apoptosis and depletion of Brca1-deficient bulge SCs. Our data reveal a major difference in the requirement of BRCA1 between different types of epidermal SCs and progenitors and during the different activation stages of adult HF SCs.