LARP7

Official Full Name

La ribonucleoprotein 7, transcriptional regulator

Organism

Homo sapiens

GeneID

51574

Background

This gene encodes a protein which is found in the 7SK snRNP (small nuclear ribonucleoprotein). This snRNP complex inhibits a cyclin-dependent kinase, positive transcription elongation factor b, which is required for paused RNA polymerase II at a promoter to begin transcription elongation. A pseudogene of this gene is located on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

Synonyms

ALAZS; PIP7S; hLARP7; HDCMA18P;

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Detailed Information

Recent Progress

LARP7, a member of the La-related proteins (LARPs), shares a conserved La module comprising the La-motif (LAM) and the RNA-recognition motif (RRM1), binding exclusively to the non-coding RNA 7SK. LARP7 is localized to the cytosol & nucleoplasm (Fig.1). LARP7 is a component of the small nuclear ribonucleoprotein (7SKsnRNP) that is required for the stability and function of the RNA, and implicated in the transcription termination and regulation of translation. The protein LARP7 is required for the integrity of inactive 7SK snRNP, in which a reservoir of P-TEFb (positive transcription elongation factor b that stimulates transcriptional elongation) is sequestered. It was shown that P-TEFb activity is important for the epithelial mesenchymal transition (EMT) and breast cancer progression. Moreover, decreased levels of LARP7 and 7SK snRNA redistribute P-TEFb to the transcriptionally active super elongation complex, resulting in P-TEFb activation and increased transcription of EMT transcription factors, which may promote breast cancer EMT, invasion, and metastasis. Another study provided new insights into the understanding of the recognition mechanism between the La module of LARP7 and RNA 7SK, whose results suggested that the E130A mutant may have an important effect on the RNA binding, which is consistent with site-directed mutagenesis.

LARP7 Fig. 1. LARP7 in human cells. (MC Rue et al, 2017)

LARP7 attracts interest from researchers due to its unique clinical significance. LARP7 also proved its significance in forming the reverse transcriptase complex telomerase. Loss of function in genes concerning telomere maintenance results in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation. The catalytic subunit TERT must be assembled properly with its telomerase RNA for telomerase to function, and previous studies have indicated that p65, a LARP7 family protein, utilizes its C-terminal xRRM domain to promote assembly of the telomerase ribonucleoprotein (RNP) complex. However, LARP7-dependent telomerase complex assembly has been considered as unique to ciliates that utilize RNA polymerase III to transcribe telomerase RNA.

Another study indicated the importance of LARP7 in cyclin dependent kinase (Cdk) 9 function, which acts through P-TEFb complex to activate and expand transcription through RNA polymerase II. Cdk9 has been shown to regulate cardiomyocyte hypertrophy, with recent evidence linking it to cardiomyocyte proliferation. It was revealed that knockdown of Larp7 increases phosphorylation of Ser2 in RNA polymerase II and increases cardiomyocyte proliferation. Larp7 knockdown also rescued the structural and functional phenotype associated with knockdown of Cdk9. The balance of Cdk9 and Larp7 plays a key role in cardiomyocyte proliferation and response to injury. Larp7 thus represents a potentially novel therapeutic target to promote cardiomyocyte proliferation and recovery from injury.

In further investigation, researchers studied the effects of LARP7 silencing in human cells in two distinct families with Alazami syndrome (which is due to a loss of function of LARP7). It was found that depletion of LARP7 caused a reduction in telomerase enzymatic activity and increasingly shorter telomeres in human cancer cell lines. Further, wild-type offspring of LARP7 mutant individuals also had shorter telomeres. Together, these findings demonstrated that in addition to the readily apparent developmental disorder associated with LARP7 deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals.

References:

Cheng, Yulan, et al. "LARP7 is a potential tumor suppressor gene in gastric cancer." Laboratory investigation; journal of technical methods and pathology 92.7(2012):1013-9.
Ji, X., et al. "LARP7 suppresses P-TEFb activity to inhibit breast cancer progression and metastasis. " eLife,3,(2014-07-18) 3.16(2014):e02907.
Krueger, Brian J., et al. "LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated." Nucleic Acids Research 36.7(2008):2219-29.
Gianfranco, Matrone, et al. "CDK9 and its repressor LARP7 modulate cardiomyocyte proliferation and response to injury in the zebrafish heart." Journal of Cell Science 128.24(2015):4560-4571.
Muniz, Lisa, S. Egloff, and T. Kiss. "RNA elements directing in vivo assembly of the 7SK/MePCE/Larp7 transcriptional regulatory snRNP." Nucleic Acids Research 41.8(2013):4686-4698.

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