BRCA1/2半缺失：探索失去一个等位基因的影响。
BRCA1/2 haploinsufficiency: exploring the impact of losing one allele.
发表日期：2023 Sep 13
作者：
Anna Minello, Aura Carreira
来源：
JOURNAL OF MOLECULAR BIOLOGY
摘要：
自从20世纪末被发现以来，对肿瘤抑制蛋白BRCA1和BRCA2功能的阐明取得了重要进展。这些蛋白在维持基因组完整性方面起着重要作用，包括DNA修复、复制叉结保护和染色体维持等。已经确立了GERMLINE突变在BRCA1和BRCA2中增加乳腺和卵巢癌风险的事实；然而，在这种情况下导致肿瘤形成的精确机制尚未完全理解。与长期以来认为第二个野生型等位基因丧失对于肿瘤发展是必要的观点相反，越来越多的证据表明即使存在一个功能等位基因，肿瘤发生也是可能的。这意味着在BRCA1/2中的杂合型表现出偏不足型，其中单个基因副本不足以完全抑制肿瘤形成。在这里，我们概述了关于BRCA偏不足的研究结果和持续的争论。我们进一步提出了研究这个课题所面临的挑战，并讨论了它在预防和治疗与BRCA相关的癌症中的潜在相关性。版权所有©2023年爱思唯尔有限公司。保留所有权利。
Since their discovery in the late 20th century, significant progress has been made in elucidating the functions of the tumor suppressor proteins BRCA1 and BRCA2. These proteins play vital roles in maintaining genome integrity, including DNA repair, replication fork protection, and chromosome maintenance. It is well-established that germline mutations in BRCA1 and BRCA2 increase the risk of breast and ovarian cancer; However, the precise mechanism underlying tumor formation in this context is not fully understood. Contrary to the long-standing belief that the loss of the second wild-type allele is necessary for tumor development, a growing body of evidence suggests that tumorigenesis can occur despite the presence of a single functional allele. This entails that heterozygosity in BRCA1/2 confers haploinsufficiency, where a single copy of the gene is not sufficient to fully suppress tumor formation. Here we provide an overview of the findings and the ongoing debate regarding BRCA haploinsufficiency. We further put out the challenges in studying this topic and discuss its potential relevance in the prevention and treatment of BRCA-related cancers.Copyright © 2023 Elsevier Ltd. All rights reserved.