Current understanding of CREPT and p15RS, carboxy-terminal domain (CTD)-interacting proteins, in human cancers

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Searching for new regulators for cancers remains great interesting in the scientific community. Our group has identified a novel oncogene CREPT, also named RPRD1B, in human, mice and chicken [1]. This gene encodes CREPT protein, with a highly conserved sequence to p15RS. Both CREPT and p15RS belong to RPRD (Regulation of nuclear pre-mRNA-domain-containing) protein family including RPRD2 [2], Cids1 in nematode, Rtt103 in budding yeast and Rhn1 in fission yeast [3].

RPRD proteins contain C-terminal domain (CTD)-interacting domains (CID) that bind to the CTD of Rpb1, the largest subunit of RNA polymerase II (RNAPII) [2]. We and others revealed that this family proteins regulates transcription. Rtt103 was reported to regulate transcriptional termination in Torpedo model [4]. However, CREPT and p15RS also regulate transcription on the promoter regions of genes. We revealed that p15RS is an intrinsic inhibitor of gene transcription by disrupting the interactions between β-catenin and TCF4 and recruiting HDAC2 onto gene promoters to enhance histone 3 deacetylation [5, 6]. On the contrary, CREPT promotes gene transcription through interacting with specific transcription factors and enhancing histone modification for the accessibility of the RNAPII complex [7, 8]. Additionally, CREPT induces a transcription loop formed by the sequences of termination and promoter regions [1]. CREPT and p15RS also interact with different phosphorylated CTDs and are able to alter CTD modifications by cooperating with other factors such as a phosphatase RPAP2 [9, 10].

Intriguingly, we and other groups observed that CREPT promoted, but p15RS repressed, tumor cell proliferation [8, 11, 12, 13]. It was observed that p15RS was inversely correlated with the N/M classification and distance metastasis, and patients with lower p15RS expression showed a shorter survival rate [11, 12]. However, CREPT was showed to be abundantly expressed in tumors and its expression negatively correlates to patient survival [8, 14, 15]. The role of CREPT in tumors may not only attribute to its regulation on transcription but also in DNA damage repair. CREPT was also reported to participate in DNA damage repairing process including DNA mismatch repair (MMR)[16]and double-strand break (DSB)-repair [17, 18]. In this review, we summarized the current understanding of the roles of CREPT and p15RS in tumors and the underlying mechanisms. We expect that revealing the functions of RPRD proteins will not only deepen our knowledge on gene transcription and DNA damage repair regulations, but also shed lights on discovery of new target for diagnosis and therapy of cancers.

References

1          Lu D, Wu Y, Wang Y, Ren F, Wang D, Su F, et al. CREPT accelerates tumorigenesis by regulating the transcription of cell-cycle-related genes. Cancer Cell. 2012; 21: 92-104.

2          Ni Z, Olsen JB, Guo X, Zhong G, Ruan ED, Marcon E, et al. Control of the RNA polymerase II phosphorylation state in promoter regions by CTD interaction domain-containing proteins RPRD1A and RPRD1B. Transcription. 2011; 2: 237-242.

3          Sugiyama T, Sugioka-Sugiyama R, Hada K, Niwa R. Rhn1, a nuclear protein, is required for suppression of meiotic mRNAs in mitotically dividing fission yeast. PLoS One. 2012; 7: e42962.

4          Kim M, Krogan NJ, Vasiljeva L, Rando OJ, Nedea E, Greenblatt JF, et al. The yeast Rat1 exonuclease promotes transcription termination by RNA polymerase II. Nature. 2004; 432: 517-522.

5          Wu Y, Zhang Y, Zhang H, Yang X, Wang Y, Ren F, et al. p15RS attenuates Wnt/{beta}-catenin signaling by disrupting {beta}-catenin.TCF4 Interaction. J Biol Chem. 2010; 285: 34621-34631.

6          Liu C, Zhang Y, Li J, Wang Y, Ren F, Zhou Y, et al. p15RS/RPRD1A (p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A) interacts with HDAC2 in inhibition of the Wnt/beta-catenin signaling pathway. J Biol Chem. 2015; 290: 9701-9713.

7          Zhang Y, Liu C, Duan X, Ren F, Li S, Jin Z, et al. CREPT/RPRD1B, a recently identified novel protein highly expressed in tumors, enhances the beta-catenin.TCF4 transcriptional activity in response to Wnt signaling. J Biol Chem. 2014; 289: 22589-22599.

8          Zhang Y, Wang S, Kang W, Liu C, Dong Y, Ren F, et al. CREPT facilitates colorectal cancer growth through inducing Wnt/beta-catenin pathway by enhancing p300-mediated beta-catenin acetylation. Oncogene. 2018; 37: 3485-3500.

9          Ali I, Ruiz DG, Ni Z, Johnson JR, Zhang H, Li PC, et al. Crosstalk between RNA Pol II C-Terminal Domain Acetylation and Phosphorylation via RPRD Proteins. Mol Cell. 2019.

10        Ni Z, Xu C, Guo X, Hunter GO, Kuznetsova OV, Tempel W, et al. RPRD1A and RPRD1B are human RNA polymerase II C-terminal domain scaffolds for Ser5 dephosphorylation. Nat Struct Mol Biol. 2014; 21: 686-695.

11        Zhang X, Cao Q, Liu X, Liu S, Wang J, Sun S, et al. Cellular and molecular evidence for malignancy-inhibitory functions of p15RS. Cell Cycle. 2012; 11: 1988-1998.

12        Ren L, Chen H, Song J, Chen X, Lin C, Zhang X, et al. MiR-454-3p-Mediated Wnt/beta-catenin Signaling Antagonists Suppression Promotes Breast Cancer Metastasis. Theranostics. 2019; 9: 449-465.

13        Ding L, Yang L, He Y, Zhu B, Ren F, Fan X, et al. CREPT/RPRD1B associates with Aurora B to regulate Cyclin B1 expression for accelerating the G2/M transition in gastric cancer. Cell Death Dis. 2018; 9: 1172.

14        Zheng G, Li W, Zuo B, Guo Z, Xi W, Wei M, et al. High expression of CREPT promotes tumor growth and is correlated with poor prognosis in colorectal cancer. Biochem Biophys Res Commun. 2016; 480: 436-442.

15        Ma D, Zou Y, Chu Y, Liu Z, Liu G, Chu J, et al. A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer. Theranostics. 2020; 10: 3708-3721.

16        Patidar PL, Motea EA, Fattah FJ, Zhou Y, Morales JC, Xie Y, et al. The Kub5-Hera/RPRD1B interactome: a novel role in preserving genetic stability by regulating DNA mismatch repair. Nucleic Acids Res. 2016; 44: 1718-1731.

17        Morales JC, Richard P, Rommel A, Fattah FJ, Motea EA, Patidar PL, et al. Kub5-Hera, the human Rtt103 homolog, plays dual functional roles in transcription termination and DNA repair. Nucleic Acids Res. 2014; 42: 4996-5006.

18        Motea EA, Fattah FJ, Xiao L, Girard L, Rommel A, Morales JC, et al. Kub5-Hera (RPRD1B) Deficiency Promotes "BRCAness" and Vulnerability to PARP Inhibition in BRCA-proficient Breast Cancers. Clin Cancer Res. 2018; 24: 6459-6470.

 

Zhijie Chang

Professor, Tsinghua University

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