Heterogeneous ribonucleoprotein particle
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are complexes of
hnRNPs are also integral to the 40S subunit of the ribosome and therefore important for the translation of mRNA in the cytoplasm.[2] However, hnRNPs also have their own nuclear localization sequences (NLS) and are therefore found mainly in the nucleus. Though it is known that a few hnRNPs shuttle between the cytoplasm and nucleus, immunofluorescence microscopy with hnRNP-specific antibodies shows nucleoplasmic localization of these proteins with little staining in the nucleolus or cytoplasm.[3] This is likely because of its major role in binding to newly transcribed RNAs. High-resolution immunoelectron microscopy has shown that hnRNPs localize predominantly to the border regions of chromatin, where it has access to these nascent RNAs.[4]
The proteins involved in the hnRNP complexes are collectively known as heterogeneous ribonucleoproteins. They include
Role in cell cycle and DNA damage
hnRNPs affect several aspects of the cell cycle by recruiting, splicing, and co-regulating certain cell cycle control proteins. Much of hnRNPs' importance to cell cycle control is evidenced by its role as an oncogene, in which a loss of its functions results in various common cancers. Often, misregulation by hnRNPs is due to splicing errors, but some hnRNPs are also responsible for recruiting and guiding the proteins themselves, rather than just addressing nascent RNAs.
BRCA1
hnRNP C is a key regulator of the BRCA1 and BRCA2 genes. In response to ionizing radiation, hnRNP C partially localizes to the site of DNA damage, and when depleted, S-phase progression of the cell is impaired.[8] Additionally, BRCA1 and BRCA2 levels fall when hnRNP C is lost. BRCA1 and BRCA2 are crucial tumor-suppressor genes which are strongly implicated in breast cancers when mutated. BRCA1 in particular causes G2/M cell cycle arrest in response to DNA damage via the CHEK1 signaling cascade.[9] hnRNP C is important for the proper expression of other tumor suppressor genes including RAD51 and BRIP1 as well. Through these genes, hnRNP is necessary to induce cell-cycle arrest in response to DNA damage by ionizing radiation.[7]
HER2
p53
hnRNPs also play a role in DNA damage response in coordination with
p53 regulates a large group of RNAs that are not translated into protein, called large intergenic noncoding RNAs (lincRNAs). p53 suppression of genes is often carried out by a number of these lincRNAs, which in turn have been shown to act though hnRNP K. Through physical interactions with these molecules, hnRNP K is targeted to genes and transmits p53 regulation, thus acting as a key repressor within the p53-dependent transcriptional pathway.[13][14]
Functions
hnRNP serves a variety of processes in the cell, some of which include:
- Preventing the folding of pre-mRNA into secondary structures that may inhibit its interactions with other proteins.
- Possible association with the splicing apparatus.
- Transport of mRNA out of the nucleus.
The association of a pre-mRNA molecule with a hnRNP particle prevents formation of short secondary structures dependent on base pairing of complementary regions, thereby making the pre-mRNA accessible for interactions with other proteins.
CD44 Regulation
hnRNP has been shown to regulate CD44, a cell-surface glycoprotein, through splicing mechanisms. CD44 is involved in cell-cell interactions and has roles in cell adhesion and migration. Splicing of CD44 and the functions of the resulting isoforms are different in breast cancer cells, and when knocked down, hnRNP reduced both cell viability and invasiveness.[15]
Telomeres
Several hnRNPs interact with telomeres, which protect the ends of chromosomes from deterioration and are often associated with cell longevity. hnRNP D associates with the G-rich repeat region of the telomeres, possibly stabilizing the region from secondary structures which would inhibit telomere replication.[16]
hnRNP has also been shown to interact with telomerase, the protein responsible for elongating telomeres and prevent their degradation. hnRNPs C1 and C2 associate with the RNA component of telomerase, which improves its ability to access the telomere.[17][18][19]
Examples
Human genes encoding heterogeneous nuclear ribonucleoproteins include:
- HNRNPA2B1
- HNRNPAB
- HNRNPB1
- HNRNPC, HNRNPCL1
- HNRNPD (AUF1), HNRPDL
- HNRNPF
- HNRNPG (RBMX)
- HNRNPH1, HNRNPH2, HNRNPH3
- HNRNPI (PTB)
- HNRNPK
- HNRNPL, HNRPLL
- HNRNPM
- HNRNPP2 (FUS/TLS)
- HNRNPR
- HNRNPQ (SYNCRIP)
- HNRNPU, HNRNPUL1, HNRNPUL2, HNRNPUL3
- FMR1[20]
See also
- Messenger RNP: complex between mRNA and protein(s) present in nucleus
References
- PMID 1066686.
- S2CID 41245800.
- PMID 8352591.
- PMID 6231300.
- ISBN 978-0-7167-7601-7.
- S2CID 14883495.
- ^ PMID 18380344.
- PMID 23585894.
- S2CID 24297965.
- PMID 26367347.
- PMID 17471238.
- S2CID 16756766.
- PMID 20673990.
- PMID 28801479.
- PMID 26151392.
- PMID 10891483.
- PMID 11074006.
- PMID 11850782.
- PMID 8083209.
- ISBN 9780387325620.
Further reading
- Xie J, Lee JA, Kress TL, Mowry KL, Black DL (July 2003). "Protein kinase A phosphorylation modulates transport of the polypyrimidine tract-binding protein". Proc. Natl. Acad. Sci. U.S.A. 100 (15): 8776–81. PMID 12851456.
- Geuens T, Delphine B, Timmerman V (August 2016). "The hnRNP Family: Insights into Their Role in Health and Disease". Human Genetics. 135 (8): 851–67. PMID 27215579.
- Takimoto M, Tomonaga T, Matunis M, et al. (August 1993). "Specific binding of heterogeneous ribonucleoprotein particle protein K to the human c-myc promoter, in vitro". J. Biol. Chem. 268 (24): 18249–58. PMID 8349701.
- Watson, James D. (2004). Molecular biology of the gene. San Francisco: Pearson/Benjamin Cummings. pp. ch. 9 and 10. ISBN 978-0-8053-4635-0.