ROLE OF TANKYRASE 1/2 IN THE HYPOXIC RESPONSE

Abstract

Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2) are two proteins that form a distinct subgroup inside the PARP family. Both TNKS share 82% of its sequence and have been linked to different cellular functions such as mitotic progression, glucose metabolism, stress granule formation and Wnt signaling. Furthermore, altered levels of TNKS1 and/or TNKS2 expression have been reported in several types of cancer such as colon, lung or brain. Both tankyrases synthesize linear chains of poly(ADP-ribose) (PAR) to produce posttranslational modifications of their target proteins and also itself through automodification. PARylation by TNKS appears to be tightly linked to ubiquitination by ubiquitin E3 ligases like RNF146. Deficient angiogenesis leads to tumor hypoxia resulting in increased aggressiveness and therapeutic resistance. The adaptation to this situation is carried out by the heterodimeric transcription factors hypoxia-inducible factor (HIF). In particular, the oxygen-dependent protein HIF-1/HIF-2 and the constitutively expressed protein HIF-1 are responsible for the induction of genes that allow the adaptation and survival of cells to hypoxia.