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       Let-7 miRNA biogenesis
       kimsg7596@kaist.ac.kr        
       À̴뿱 ±³¼ö        2016.03.31 16:18        11216
´Ù¿î·Îµå : Let-7 miRNA biogenesis_À̴뿱 ±³¼ö.pdf(350 Kb)
 

 Let-7 miRNA biogenesis

 

                                                                                                            Çѱ¹°úÇбâ¼ú¿ø À̴뿱 ±³¼ö


1. °³¿ä
MicroRNA (ÀÌÇÏ miRNA)´Â ¾à 22 nucleotide ±æÀÌÀÇ noncoding RNA·Î¼­ ´Ù¾çÇÑ ÁøÇÙ »ý¹°¿¡¼­ ´Ù¾çÇÑ À¯ÀüÀÚÀÇ ¹ßÇöÀ» Á¶ÀýÇÏ´Â °ÍÀ¸·Î ¾Ë·ÁÁ® ÀÖ´Ù. MiRNA´Â mRNAÀÇ 3¡¯UTR¿¡ ÀÖ´Â »óº¸ÀûÀÎ ¼­¿­°úÀÇ °áÇÕÀ» ÅëÇØ Ç¥Àû mRNAÀÇ Àü»ç ¹æÇØ, ´Ü¹éÁú·ÎÀÇ ¹ø¿ª ¾ïÁ¦, mRNAÀÇ ºÐÇØ µîÀÇ ¿©·¯ °¡Áö ¹æ¹ýÀ¸·Î Ç¥Àû À¯ÀüÀÚÀÇ ¹ßÇöÀ» ¾ïÁ¦ÇÑ´Ù. ´ëÇ¥ÀûÀÎ miRNAÀÎ let-7 miRNA´Â C. elegance¿¡¼­ óÀ½À¸·Î ¹ß°ßµÈ miRNA Áß Çϳª·Î¼­ C. elegans (¿¹»Û²¿¸¶¼±Ãæ)ÀÇ ¹ß´Þ ½ÃÁ¡À» Á¶ÀýÇÏ´Â ¿ªÇÒÀ» Çϸç C. elegans »Ó¸¸ ¾Æ´Ï¶ó ÃÊÆĸ®, Æ÷À¯·ù¿¡µµ Á¸ÀçÇÏ°í ±× ¿ªÇÒÀÌ ÁøÈ­ÀûÀ¸·Î Àß º¸Á¸µÇ¾î ÀÖ´Â °ÍÀ¸·Î ¾Ë·ÁÁ® ÀÖ´Ù. Let-7 ÀÇ ¹ßÇöÀº Æ÷À¯·ùÀÇ ¹ß´Þ °úÁ¤¿¡¼­ Áõ°¡ÇÏ´Â °ÍÀ¸·Î ¾Ë·ÁÁ® ÀÖÀ¸¸ç ´Ù¸¥ ¿©·¯ »ý¹°ÇÐÀû °úÁ¤¿¡ °ü¿©ÇÑ´Ù´Â »ç½Çµµ ¾Ë·ÁÁ® ÀÖ´Ù. ¶ÇÇÑ Á¤»óÀûÀÎ ¹ß´Þ°úÁ¤»Ó¸¸ ¾Æ´Ï¶ó ƯÁ¤ ¾Ï ¼¼Æ÷¿¡¼­µµ let-7 ÀÇ ¹ßÇöÀÌ Áõ°¡ÇÑ´Ù´Â »ç½Ç·Î ¹Ì·ç¾îº¸¾Æ let-7ÀÇ ¹ßÇö Á¶ÀýÀÌ ¸Å¿ì Áß¿äÇÏ´Ù°í À¯ÃßÇÒ ¼ö ÀÖÀ¸¸ç ÀÌ Á¶Àý°úÁ¤¿¡ LIN28ÀÌ ¸Å¿ì Áß¿äÇÑ ¿ªÇÒÀ» ÇÏ´Â °ÍÀ¸·Î ¾Ë·ÁÁ® ÀÖ´Ù.


À¯µµ¸¸´ÉÁٱ⼼Æ÷ÀÇ ÁÖ¿ä ÀÎÀÚ Áß ÇϳªÀÎ LIN28Àº Àΰ£, Áã¿Í °°Àº Æ÷À¯·ù¿¡¼­ LIN28A¿Í LIN28BÀÇ µÎ °¡Áö ÇüÅ°¡ Á¸ÀçÇϸç Áٱ⼼Æ÷ÀÇ ÀÚ±âÀç»ý°ú ÀüºÐÈ­´É ±×¸®°í ºÐÈ­¿Í ¹ß´Þ°úÁ¤À» Á¶ÀýÇÏ´Â Áß¿äÇϸç, ¼¼Æ÷¼ºÀå Á¶Àý¿¡ °áÁ¤ÀûÀÎ c-Myc À¯ÀüÀÚ ¹ßÇöÀ» Á¶ÀýÇÏ¿© Áٱ⼼Æ÷»Ó¸¸ ¾Æ´Ï¶ó ¾Ï¼¼Æ÷ÀÇ Á¶Àý¿¡µµ °ü¿©ÇÑ´Ù. Let-7 Àº ¿©·¯ ´Ü°èÀÇ °¡°ø °úÁ¤À» ÅëÇØ ¼º¼÷ let-7 miRNA¸¦ »ý¼ºÇϴµ¥, LIN28Àº ¿©·¯ ´Ü°èÀÇ let-7 ¼º¼÷°úÁ¤À» Á¶ÀýÇÔÀ¸·Î½á ¼¼Æ÷¼ºÀåÀ» Á¶ÀýÇÏ´Â °ÍÀ¸·Î ¾Ë·ÁÁ® ÀÖ´Ù. ÀÌ·± »ç½ÇÀ» ÅëÇØ LIN28¿¡ ÀÇÇÑ let-7ÀÇ ¼º¼÷ ÀúÇØ Á¶Àý±âÀü¿¡ ´ëÇÑ ¿¬±¸´Â ¹è¾ÆÁٱ⼼Æ÷ÀÇ ÀüºÐÈ­´ÉÀ» À¯Áö»Ó¸¸ ¾Æ´Ï¶ó Ç×¾ÏÄ¡·á µîÀÇ ÀÓ»ó ´Ü°è±îÁö Æø ³Ð°Ô ÀÀ¿ëÇÒ ¼ö ÀÖÀ» °ÍÀ¸·Î ±â´ëµÈ´Ù.

 

2. Let-7 miRNAÀÇ ¼º¼÷°úÁ¤
Let-7 miRNA´Â ÀϹÝÀûÀÎ miRNA¿Í À¯»çÇÏ°Ô µÎ Á¾·ùÀÇ °¡°øÈ¿¼ÒÀÎ Drosha¿Í Dicer¿¡ ÀÇÇÑ ¼º¼÷ °úÁ¤À» °ÅÄ£´Ù. Let-7 Àº mRNA¿Í °°ÀÌ ÇÙ ³»¿¡¼­ RNA ÁßÇÕÈ¿¼Ò II¿¡ ÀÇÇØ Àü»çµÇ¾î 5¡¯ capping°ú 3¡¯ poly(A) tailÀ» °¡Áö¸ç (Bracht et al., 2004), Àü»çü ³»ºÎÀÇ »óº¸Àû °áÇÕÀ» ÅëÇØ hairpin stem-loopÀÇ ±¸Á¶Àû Ư¡À» °¡Áø primary let-7 (ÀÌÇÏ pri-let-7)À» Çü¼ºÇÑ´Ù. ÀÌ pri-let-7 Àº Drosha¿Í DGCR8À¸·Î ÀÌ·ç¾îÁø RNAºÐÇØÈ¿¼Ò º¹ÇÕü¿¡ ÀÇÇØ ¾à 60~70 nucleotide Å©±âÀÇ precursor let-7 (ÀÌÇÏ pre-let-7)À» Çü¼ºÇϴµ¥ pri-let-7 °ú ¸¶Âù°¡Áö·Î stem-loopÀ̶ó´Â ±¸Á¶Àû Ư¡À» °¡Áö°í ÀÖÀ¸¸ç 3¡¯ ¸»´Ü 1 ȤÀº 2 nucleotide ±æÀÌÀÇ overhangÀ» Áö´Ñ´Ù (Lee et al., 2003; Denli et al., 2004; Gregory et al., 2004; Landthaler et al., 2004).

 

Figure 1. Let-7 miRNA ¼º¼÷°úÁ¤ (Lee et al., 2015)


Drosha¿¡ ÀÇÇØ °¡°øµÈ pre-let-7Àº Ran-GTP ÀÇÁ¸Àû ¼ö¼ÛüÀÎ exportin 5¿¡ ÀÇÇØ ÇÙ¿¡¼­ ¼¼Æ÷Áú·Î À̵¿µÇ¸ç ÀÌ °÷¿¡¼­ µÎ ¹ø° °¡°øÈ¿¼ÒÀÎ Dicer¿¡ ÀÇÇØ Ãß°¡ÀûÀÎ ¼º¼÷ °úÁ¤À» °ÅÄ¡¸é¼­ ¾à 22 nucleotide ±æÀÌÀÇ ¼º¼÷ let-7 À» Çü¼ºÇÑ´Ù (Bernstein et al., 2001; Grishok et al., 2001; Hutvagner et al., 2001; Ketting et al., 2001; Knight and Bass, 2001). Dicer´Â 3¡¯ ¸»´Ü¿¡ 2 nucleotide overhangÀ» °¡Áø precursor¸¦ ¼±È£Çϱ⠶§¹®¿¡ 1 nucleotide overhangÀ» °¡Áø ÀϺΠpre-let-7ÀÇ °æ¿ì Ãß°¡ÀûÀÎ °úÁ¤ÀÌ ´õ ÇÊ¿äÇÏ´Ù. ÀÌ °æ¿ì 3¡¯ ¸»´ÜÀÌ ÅÔÈ¿¼Ò (TUTase, Terminal Uridylyl Transferase)¿¡ ÀÇÇØ ¸ð³ëÀ¯¸®µôÈ­ µÊÀ¸·Î½á Dicer°¡ ¼±È£ÇÏ´Â 2 nucleotide±æÀÌÀÇ 3¡¯ ¸»´Ü overhangÀ» ¸¸µé¾î Dicer¿¡ ÀÇÇÑ ¼º¼÷°úÁ¤À» µ½´Â´Ù (Heo et al., 2012). ÀÌÈÄ »ý¼ºµÈ ¼º¼÷ let-7 Àº Argonaute¿Í ÇÔ²² Ç¥Àû mRNA°úÀÇ »óº¸Àû °áÇÕÇÔÀ¸·Î½á Ç¥Àû mRNAÀÇ ¹ßÇöÀ» ÀúÇØÇÏ´Â ¿ªÇÒÀ» ¼öÇàÇÑ´Ù.

 

3. LIN28¿¡ ÀÇÇÑ let-7 miRNA ¼º¼÷ÀÇ Á¶Àý
Áö±Ý±îÁö ¿¬±¸ °á°ú¿¡ µû¸£¸é let-7 miRNAÀÇ ¼º¼÷°úÁ¤ÀÇ Á¶ÀýÀº Å©°Ô µÎ Á¾·ù·Î ³ª´­ ¼ö Àִµ¥ ÀÌ µÎ °úÁ¤ ¸ðµÎ LIN28¿¡ ÀÇÇØ ÀÌ·ç¾îÁö´Â °ÍÀ¸·Î ¾Ë·ÁÁ® ÀÖ´Ù. ¸ÕÀú LIN28A¸¦ HEK293T ¼¼Æ÷ÁÖ¿¡¼­ °ú¹ßÇö ÇÒ °æ¿ì pre-let-7 ÀÇ 3¡¯ ¸»´ÜÀÌ ÅÔÈ¿¼Ò¿¡ ÀÇÇØ ¿Ã¸®°íÀ¯¸®µôÈ­ µÈ´Ù´Â »ç½ÇÀÌ ¾Ë·ÁÁ³À¸¸ç (Heo et al., 2008; Hagan et al., 2009; Heo et al., 2009), ¿Ã¸®°íÀ¯¸®µôÈ­ µÈ pre-let-7 Àº Dicer¿¡ ÀÇÇÑ ¼º¼÷ÀÌ ÀúÇصǴ ´ë½Å¿¡ ¿ÀÈ÷·Á DIS3L2¿¡ ÀÇÇØ ºÐÇصÊÀ¸·Î½á ¼º¼÷ let-7 ÀÌ »ý¼ºµÇÁö ¸øÇϵµ·Ï ÇÑ´Ù (Chang et al., 2013; Malecki et al., 2013; Ustianenko et al., 2013). ¹Ý¸é LIN28A°¡ ¾ø´Â »óȲ¿¡¼­´Â pre-let-7 ÀÌ ¸ð³ëÀ¯¸®µôÈ­ µÇ¸é¼­ Dicer¿¡ ÀÇÇØ ¼º¼÷ let-7 À» ¸¸µé¾î³½´Ù. ÀÌ·± Çö»óÀº HEK293T ¼¼Æ÷ÁÖ»Ó¸¸ ¾Æ´Ï¶ó ¹è¾ÆÁٱ⼼Æ÷¿Í ƯÁ¤ ¾Ï¼¼Æ÷¿¡¼­µµ ÀϾ´Ù´Â »ç½ÇÀÌ ¾Ë·ÁÁ³´Ù.

 

 

Figure 2. Let-7 miRNA ¼º¼÷°úÁ¤ÀÇ Á¶Àý (Lee et al., 2015)


LIN28B´Â LIN28A¿Í ´Ù¸£°Ô ÅÔÈ¿¼Ò-ºñÀÇÁ¸ÀûÀ¸·Î let-7ÀÇ ¼º¼÷À» ÀúÇØÇÑ´Ù (Piskounova et al., 2011). ÇÙ¿¡ ÁÖ·Î Á¸ÀçÇÏ´Â LIN28B´Â LIN28A¿Í °°ÀÌ RNA¿Í Á÷Á¢ °áÇÕÇÒ ¼ö ÀÖ´Â µµ¸ÞÀÎÀ» °¡Áö°í ÀÖÁö¸¸, LIN28A¿Í ´Þ¸® ÇÙ ³» ¼¼Æ÷ ¼Ò±â°üÀÎ ÀÎÀ¸·Î À̵¿ÇÒ ¼ö ÀÖ´Â NoLS (Nucleolar-Localization Signal)À» °¡Áö°í ÀÖ´Ù. ÀÌ·± LIN28BÀÇ Æ¯Â¡À¸·Î ÀÎÇØ, ÇÙ ³»¿¡¼­ pri-let-7 °ú Á÷Á¢ °áÇÕÇÑ LIN28B´Â Dicer°¡ ¾ø´Â ÀÎÀ¸·Î pri-let-7 °ú ÇÔ²² À̵¿ÇÔÀ¸·Î½á Dicer¿¡ ÀÇÇÑ Ãß°¡ÀûÀÎ let-7ÀÇ ¼º¼÷°úÁ¤ÀÌ ÀϾ ¼ö ¾ø°Ô ÇÔÀ¸·Î½á ÅÔÈ¿¼Ò-ÀÇÁ¸ÀûÀ¸·Î let-7ÀÇ ¼º¼÷À» ¸·´Â LIN28A°ú´Â ´Ù¸¥ ¹æ¹ýÀ¸·Î ¼º¼÷ let-7 »ý¼ºÀ» ¾ïÁ¦ÇÑ´Ù.


ÃÖ±Ù ¿¬±¸¿¡ ÀÇÇϸé LIN28Aµµ LIN28B¿Í À¯»çÇÏ°Ô ÅÔÈ¿¼Ò-ºñÀÇÁ¸ÀûÀ¸·Î ¼º¼÷ let-7ÀÇ »ý¼ºÀ» ÀúÇØÇÒ ¼ö ÀÖ´Ù´Â »ç½ÇÀÌ ¹àÇôÁ³´Ù (Kim et al., 2014). LIN28A´Â ÁÖ·Î ¼¼Æ÷Áú¿¡ Á¸ÀçÇÏÁö¸¸ ÀϺΠÇÙ ³»¿¡µµ Á¸ÀçÇϴµ¥, ÇÙ ³»¿¡¼­ È÷½ºÅæ ¸ð³ë¸ÞÆ¿È­ È¿¼ÒÀÎ SET7/9°úÀÇ °áÇÕÀ» ÅëÇØ 135¹ø° ¶óÀ̽ſ¡ ƯÀÌÀûÀ¸·Î ¸ð³ë¸ÞÆ¿È­ µÈ´Ù. ÀÌ ¸ð³ë¸ÞÆ¿È­µÈ ÇÙ ³» LIN28A´Â ¿¡¼­ pri-let-7 °ú ´ÙÁß º¹ÇÕü Çü¼ºÀ» ÃËÁøÇÏ°í LIN28B¿Í À¯»çÇÏ°Ô ÀÎÀ¸·Î À̵¿ÇÔÀ¸·Î½á pri-let-7 ÀÌ Dicer¿¡ ÀÇÇØ ¼º¼÷µÇ´Â °ÍÀ» ÀúÇØÇÑ´Ù. ¶ÇÇÑ LIN28B°¡ ¹ßÇöµÇ´Â ƯÁ¤ ¾Ï¼¼Æ÷ÀÇ °æ¿ì LIN28B ¿ª½Ã LIN28A¿Í À¯»çÇÏ°Ô DIS3L2¿Í »óÈ£ÀÛ¿ëÇÏ´Â »ç½ÇÀÌ Ãß°¡ÀûÀ¸·Î ¹àÇôÁ³´Ù (Suzuki et al., 2015). ÀÌ·± ÃÖ±ÙÀÇ ¿¬±¸°á°ú·Î ¹Ì·ç¾îº¸¾Æ LIN28A¿Í LIN28BÀÇ let-7 ¼º¼÷ ÀúÇØ °úÁ¤ÀÌ ¾î´À Á¤µµ °øÅëÀûÀÎ ±âÀüÀ» ÅëÇؼ­ ÀÌ·ç¾îÁú °ÍÀÌ¶ó ¿¹»óµÇ¸ç ÀÌ¿¡ ´ëÇÑ Èļӿ¬±¸°¡ ÇÊ¿äÇÏ´Ù.

 

 

4. °íÂû
Let-7 miRNA´Â Áٱ⼼Æ÷ÀÇ ºÐÈ­¸¦ ÃËÁøÇÏ¸ç ¼¼Æ÷¼ºÀåÀ» Á¶ÀýÇÏ´Â ¿ªÇÒÀ» ÇÑ´Ù. µû¶ó¼­ let-7 miRNAÀÇ Á¶Àý°úÁ¤¿¡ ´ëÇÑ ¿¬±¸´Â ¹è¾ÆÁٱ⼼Æ÷ÀÇ ÀüºÐÈ­´ÉÀÇ Á¶ÀýÀ» ÀÌÇØÇÏ´Â µ¥ ¸Å¿ì Áß¿äÇÏ´Ù. »Ó¸¸ ¾Æ´Ï¶ó LIN28AÀÌ À¯µµ¸¸´ÉÁٱ⼼Æ÷ Á¦ÀÛ¿¡ ÇÊ¿äÇÑ ÁÖ¿ä ¿ä¼ÒÀÓÀ» °¨¾ÈÇÒ ¶§, let-7 miRNAÀÇ ¼º¼÷°úÁ¤¿¡ ´ëÇÑ ¿¬±¸¸¦ ÅëÇØ ÇöÀç ¸Å¿ì ³·Àº À¯µµ¸¸´ÉÁٱ⼼Æ÷ Á¦ÀÛÀÇ È¿À²À» Áõ´ë½Ãų ¼ö ÀÖ´Â »õ·Î¿î ¹æ¹ý·ÐÀ» Á¦½ÃÇÒ ¼ö ÀÖÀ¸¸®¶ó ¿¹»óµÈ´Ù. ¶ÇÇÑ ¸î¸î ¾Ï¼¼Æ÷¿¡¼­ let-7 ÀÇ ¹ßÇöÀÌ Á¤»ó¼¼Æ÷¿¡ ºñÇØ Áõ°¡ÇÑ´Ù´Â »ç½Ç°ú LIN28 ¿ª½Ã ¾Ï¼¼Æ÷¿Í ¹ÐÁ¢ÇÑ °ü·ÃÀÌ ÀÖ´Ù´Â »ç½ÇÀ» Á¾ÇÕÇغ¸¸é let-7 °ú LIN28¿¡ ´ëÇÑ ¿¬±¸´Â Ç׾Ϲ°ÁúÀÇ »õ·Î¿î Ç¥ÀûÀÇ ¹ß±¼À̳ª Ç׾Ϲ°ÁúÀÇ ½ºÅ©¸®´× µî ÀÓ»óºÐ¾ß¿¡µµ ´Ù¾çÇÏ°Ô ÀÀ¿ëµÉ ¼ö ÀÖÀ¸¸®¶ó ±â´ëµÈ´Ù.

 

5. Âü°í¹®Çå
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