SAMHD1 in cancer: curse or cure?

Abstract

Human sterile α motif and HD domain-containing protein 1 (SAMHD1), originally described as the major cellular deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) balancing the intracellular deoxynucleotide (dNTP) pool, has come recently into focus of cancer research. As outlined in this review, SAMHD1 has been reported to be mutated in a variety of cancer types and the expression of SAMHD1 is dysregulated in many cancers. Therefore, SAMHD1 is regarded as a tumor suppressor in certain tumors. Moreover, it has been proposed that SAMHD1 might fulfill the requirements of a driver gene in tumor development or might promote a so-called mutator phenotype. Besides its role as a dNTPase, several novel cellular functions of SAMHD1 have come to light only recently, including a role as negative regulator of innate immune responses and as facilitator of DNA end resection during DNA replication and repair. Therefore, SAMHD1 can be placed at the crossroads of various cellular processes. The present review summarizes the negative role of SAMHD1 in chemotherapy sensitivity, highlights reported SAMHD1 mutations found in various cancer types, and aims to discuss functional consequences as well as underlying mechanisms of SAMHD1 dysregulation potentially involved in cancer development.

Modulation of DNA Damage Response by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase (SAMHD1) Determines Prognosis and Treatment Efficacy in Different Solid Tumor Types

“…Collectively, our data confirm the key role of SAMHD1 in cancer progression but also indicates that its function might depend on the specific tumor type, being able to act as a tumor suppressor, as reported previously mainly for hematological tumors [6,7,49] or alternatively as a promoter of cancer progression. Indeed, data derived from TCGA or ICGC databases show similar results, pointing towards SAMHD1 tumor promoter function in ovarian carcinoma, but not in lung and breast carcinoma [48,50,51], in contrast with the data presented here. Differences in methods for determining SAMHD1 status, the hetero-geneity of the clinical series evaluated, and the possible different treatments that patients receive may explain the apparent contradictory results between data from databases and our data, which rely on rather small but homogenous cohorts evaluated using the same criteria across tumor types and samples.…”

Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

“…While mutation in SAMHD1 is a common somatic event in a variety of cancers [53][54][55][56][57][58][59][60][61][62][63] , it has not been described as a germline risk factor previously. Recessive inheritance of SAMHD1 missense and PTV variants have been associated with Aicardi-Goutieres syndrome, a congenital autoimmune disease 64 .…”

Targeting the DNA damage response and repair in cancer through nucleotide metabolism

“…Thus, perhaps unsurprisingly, dysregulation or mutation of SAMHD1 has been reported in several malignancies (reviewed in refs. [ 121 , 122 ]). Chronic lymphocytic leukaemia (CLL) [ 123 , 124 ], T‐cell prolymphocytic leukaemia [ 125 ], colon cancer [ 126 ] and mantle cell lymphoma [ 127 , 128 , 129 ], amongst others, have all had SAMHD1 mutations identified within.…”