Exploring ABOBEC3A and APOBEC3B substrate specificity and their role in HPV positive head and neck cancer.
Exploring ABOBEC3A and APOBEC3B substrate specificity and their role in HPV positive head and neck cancer.
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DOI：
10.1016/j.isci.2022.105077
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发表时间：
2022-10-21
期刊：
影响因子：
5.8
通讯作者：
Anderson, Karen S.
中科院分区：
文献类型：
--
作者：
Papini, Christina;Wang, Zechen;Kudalkar, Shalley N.;Schrank, Travis Parke;Tang, Su;Sasaki, Tomoaki;Wu, Cory;Tejada, Brandon;Ziegler, Samantha J.;Xiong, Yong;Issaeva, Natalia;Yarbrough, Wendell G.;Anderson, Karen S.
APOBEC 3家族成员是催化胞苷转化为尿嘧啶的胞苷脱氨酶。许多研究已经建立了APOBEC 3表达与癌症发展和进展之间的联系，特别是APOBEC 3A（A3 A）和APOBEC 3B（A3 B）。对人乳头瘤病毒阳性（HPV+）头颈部鳞状细胞癌（HNSCC）和临床试验标本的临床前研究显示，去甲基化后诱导A3 B表达，但不诱导A3 A表达。我们研究了全长A3 B的胞苷脱氨酶活性的动力学特征，发现A3 B喜欢较长的底物和−2位的嘌呤，而A3 A喜欢较短的底物和−2位的腺嘌呤或胸腺嘧啶。在HPV+ HNSCC中也确定了A3 B催化活性而不是A3 A的重要性和生物学意义，以及在-2位偏好嘌呤。我们的研究探讨了影响A3 A和A3 B相关癌症突变形成的因素，这些突变对于理解APOBEC 3相关的致癌作用和促进药物发现至关重要。A3 B在5-AzaC治疗后上调，并与HPV+ HNSCC中的5-AzaC敏感性相关全长A3 B在生物化学上偏好较长的底物和−2位点的嘌呤A3 B在HPV+和HPV− HNSCC细胞中也偏好−2位点的嘌呤A3 B在-2位点的特征与HPV+ HNSCC低吸烟者的患者存活率差相关生物科学;生物化学;癌症
APOBEC3 family members are cytidine deaminases catalyzing conversion of cytidine to uracil. Many studies have established a link between APOBEC3 expression and cancer development and progression, especially APOBEC3A (A3A) and APOBEC3B (A3B). Preclinical studies with human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) and clinical trial specimens revealed induction of A3B, but not A3A expression after demethylation. We examined the kinetic features of the cytidine deaminase activity for full length A3B and found that longer substrates and a purine at −2 position favored by A3B, whereas A3A prefers shorter substrates and an adenine or thymine at −2 position. The importance and biological significance of A3B catalytic activity rather than A3A and a preference for purine at the −2 position was also established in HPV+ HNSCCs. Our study explored factors influencing formation of A3A and A3B-related cancer mutations that are essential for understanding APOBEC3-related carcinogenesis and facilitating drug discovery. A3B is upregulated after 5-AzaC treatment and related to 5-AzaC sensitivity in HPV+ HNSCC Full-length A3B prefers longer substrates and a purine at −2 site biochemically A3B also prefers a purine at −2 site in both HPV+ and HPV− HNSCC cells A3B signature at -2 site linked to poor patient survival in HPV+ HNSCC low smokers Biological sciences; Biochemistry; Cancer
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影响因子：
30.8
作者：
Burns, Michael B.;Temiz, Nuri A.;Harris, Reuben S.
通讯作者：
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16
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作者：
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通讯作者：
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16.6
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Schiffer CA