Contributions of Rad9 to tumorigenesis

Abstract

Rad9 plays a crucial role in maintaining genomic stability by regulating cell cycle checkpoints, DNA repair, telomere stability, and apoptosis. Rad9 controls these processes mainly as part of the heterotrimeric 9-1-1 (Rad9-Hus1-Rad1) complex. However, in recent years it has been demonstrated that Rad9 can also act independently of the 9-1-1 complex as a transcriptional factor, participate in immunoglobulin class switch recombination, and show 3'-5' exonuclease activity. Aberrant Rad9 expression has been associated with prostate, breast, lung, skin, thyroid, and gastric cancers. High expression of Rad9 is causally related to, at least, human prostate cancer growth. On the other hand, deletion of Mrad9, the mouse homolog, is responsible for increased skin cancer incidence. These results reveal that Rad9 can act as an oncogene or tumor suppressor. Which of the many functions of Rad9 are causally related to initiation and progression of tumorigenesis and the mechanistic details by which Rad9 induces or suppresses tumorigenesis are presently not known, but are crucial for the development of targeted therapeutic interventions.

Figure 1. Human Rad9 structural and functional domains

Rad9 is a 391 aa protein, roughly divided into two parts; the N-terminal aa1-270 contains two PCNA-like domains, primarily involved in assembling the 9-1-1 complex, and the C-terminal tail domain aa271-391 that does not participate in the 9-1-1 complex, but binds a number of proteins crucial for its function, is highly phosphorylated, and contains a proline-rich domain (PRR) and a nuclear localization signal (NLS). Solid bars denote the position of Rad9 that interacts with the depicted proteins (shown in blue). Proteins that Rad9 interacts with, but their exact binding position is not known, are not shown. FXXLF is the Rad9 sequence that binds to AR. The functional outcome of Rad9-protein association is shown in red. Phosphorylation sites: Y28, S272, T292, S328, S387. Methylation sites: R172, R174, R175. Abbreviations are as follows: BH3: bcl-2 homology motif 3; PCNA: proliferating cell nuclear antigen; PRR: proline-rich domain; NLS: nuclear localization signal; PRMT5: protein methyltransferase 5; TLK-1B: tousled-like kinase 1B; TopBP1: topoisomerase IIb binding protein; MLH1: mutL homolog 1; CAD: carbamoyl phosphate synthetase/aspartate transcarbamoylase/dihydroorotase; AR: androgen receptor; CK2: casein kinase 2; ATM: Ataxia telangiectasia mutated; ATR: ATM and Rad3-related; CHK1: checkpoint kinase 1.