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Review
. 2024 Jun 5;13(11):980.
doi: 10.3390/cells13110980.

MATR3's Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases

Jhune Rizsan Santos  1   2 , Jeehye Park  1   2
Affiliations
Review

MATR3's Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases

Jhune Rizsan Santos et al. Cells. .

Abstract

Matrin-3 (MATR3) was initially discovered as a component of the nuclear matrix about thirty years ago. Since then, accumulating studies have provided evidence that MATR3 not only plays a structural role in the nucleus, but that it is also an active protein involved in regulating gene expression at multiple levels, including chromatin organization, DNA transcription, RNA metabolism, and protein translation in the nucleus and cytoplasm. Furthermore, MATR3 may play a critical role in various cellular processes, including DNA damage response, cell proliferation, differentiation, and survival. In addition to the revelation of its biological role, recent studies have reported MATR3's involvement in the context of various diseases, including neurodegenerative and neurodevelopmental diseases, as well as cancer. Moreover, sequencing studies of patients revealed a handful of disease-associated mutations in MATR3 linked to amyotrophic lateral sclerosis (ALS), which further elevated the gene's importance as a topic of study. In this review, we synthesize the current knowledge regarding the diverse functions of MATR3 in DNA- and RNA-related processes, as well as its involvement in various diseases, with a particular emphasis on ALS.

Keywords: DNA-binding protein; MATR3; RNA-binding protein; amyotrophic lateral sclerosis; nucleic acid binding protein.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 4
Figure 4
MATR3 is associated with various diseases. Missense mutations in MATR3 have been linked to amyotrophic lateral sclerosis (ALS; mutations in blue) as well as to neurodevelopmental disorders (NDD; mutations in green). ALS-associated mutations are located in the intrinsically disordered regions of MATR3, as predicted using the Metapredict v2 webserver (metapredict.net) [92] while missense mutations in the ordered regions were identified in NDDs. A residue having a Metapredict disorder score above 0.5 indicates that it is likely to be in an intrinsically disordered region (lilac), whereas a score below 0.5 indicates that it is likely to be in an ordered region (orange). The domains of MATR3 were indicated (zinc finger, ZnF; RNA recognition motif, RRM) and colored in turquoise.
Figure 1
Figure 1
The molecular and biological roles of MATR3. MATR3 contains a nuclear export signal (NES), a nuclear localization signal (NLS), as well as two zinc finger (ZnF) domains and two RNA recognition motifs (RRM). As a nucleic acid binding protein, MATR3 plays a role in various process associated with DNA and RNA, including the DNA damage response, chromatin looping and organization, transcription, translation, mRNA stability, modulation of noncoding RNA (ncRNA), and RNA splicing. Scaffold/matrix attachment region, S/MAR; CCCTC-binding factor, CTCF.
Figure 2
Figure 2
Proposed mechanisms of MATR3 degradation. Several studies have shown that MATR3 can be degraded through a variety of mechanisms including enzymatic cleavage mediated by calpains and a variety of caspases, and following activation of N-methyl D-aspartate (NMDA) receptor (NMDAR) or phosphorylation catalyzed by protein kinase A (PKA).
Figure 3
Figure 3
Biological functions associated with MATR3. MATR3 has been shown to play a role in maintaining or modulating the function and/or development of a variety of cell types.
Figure 5
Figure 5
The molecular and functional changes associated with the MATR3 S85C mutation. Pathological changes to MATR3 function and properties due to the missense S85C mutation include, but are not limited to, deficiencies in its normal function and impairment of its biochemical properties.
Figure 6
Figure 6
The molecular and functional changes associated with the MATR3 neurodevelopmental disease-associated mutations. Pathological changes to MATR3 function and properties due to the neurodevelopmental disease-associated missense mutation include, but are not limited to, deficiencies in its normal function and impairment of its biochemical properties.
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