Scholarlink

<p>Genetic lesions drive cancer development and progression, and understanding their origins will reveal the mechanisms of carcinogenesis. We showed that murine FAM72A promotes mutagenic DNA repair during antibody maturation by acting as a substrate adaptor of the CTLH<sup>MKLN1</sup> E3 ligase to induce the proteasome degradation of Uracil DNA glycosylase 2 (UNG2), a pivotal enzyme of the base excision repair. In humans, the <i>FAM72</i> gene has expanded to include four paralogues named <i>FAM72A-D</i>. Bioinformatic studies suggested that the human <i>FAM72</i> genes are overexpressed in a broad range of cancers. However, the functional roles of FAM72A-D in human biology and cancer are unknown. Here, we show that FAM72 family members are minimally expressed in most healthy tissues except for thymus, and that <i>FAM72A</i>, <i>B</i> and <i>D</i> are overexpressed in primary tumorigenic tissues. Human <i>FAM72</i> expression inversely correlates with UNG2 protein level in human cell lines and primary tumorigenic tissues suggesting that human FAM72 promotes UNG2 degradation. However, only FAM72A is able to bind to and induce UNG2 degradation in human cells. Our results suggest that the ability of FAM72A to induce UNG2 degradation contributes to neoplasia in a variety of cancer types by promoting mutagenic repair of genomic dUs.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

FAM72A promotes UNG2 degradation and mutagenesis in human cancer cells

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月2日

查看全文
  • Yuqing Feng,
  • Philip Barbulescu,
  • Chetan K. Chana,
  • Melika Shirdarreh,
  • Hong Yang,
  • Lizhen Wu,
  • Sami Mamand,
  • Mohammad Kashem,
  • Amin Zia,
  • Ming Han,
  • Julissa Tsao,
  • Trevor Pugh,
  • David Cescon,
  • David G. Schatz,
  • Frank Sicheri,
  • Alberto Martin,
  • Rossanna C. Pezo

摘要

Genetic lesions drive cancer development and progression, and understanding their origins will reveal the mechanisms of carcinogenesis. We showed that murine FAM72A promotes mutagenic DNA repair during antibody maturation by acting as a substrate adaptor of the CTLHMKLN1 E3 ligase to induce the proteasome degradation of Uracil DNA glycosylase 2 (UNG2), a pivotal enzyme of the base excision repair. In humans, the FAM72 gene has expanded to include four paralogues named FAM72A-D. Bioinformatic studies suggested that the human FAM72 genes are overexpressed in a broad range of cancers. However, the functional roles of FAM72A-D in human biology and cancer are unknown. Here, we show that FAM72 family members are minimally expressed in most healthy tissues except for thymus, and that FAM72A, B and D are overexpressed in primary tumorigenic tissues. Human FAM72 expression inversely correlates with UNG2 protein level in human cell lines and primary tumorigenic tissues suggesting that human FAM72 promotes UNG2 degradation. However, only FAM72A is able to bind to and induce UNG2 degradation in human cells. Our results suggest that the ability of FAM72A to induce UNG2 degradation contributes to neoplasia in a variety of cancer types by promoting mutagenic repair of genomic dUs.